Substituted pyrazolo[1,5-a]pyrimidines as calcium receptor modulating agents

ABSTRACT

There is provided a calcium receptor modulator comprising a compound of the formula (I): 
     
       
         
         
             
             
         
       
     
     wherein ring A is an optionally substituted 5- to 7-membered ring; ring B is an optionally substituted 5- to 7-membered heterocyclic ring; X 1  is CR 1 , CR 1 R 2 , N or NR 13 ; X 2  is N or NR 3 ; Y is C, CR 4  or N, Z is CR 5 , CR 5 R 6 , N or NR 7 ; Ar is an optionally substituted cyclic group; R is H, an optionally substituted hydrocarbon group, etc.; and   is a single bond or a double bond; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 13  are independently H, an optionally substituted hydrocarbon group; or a salt thereof or a prodrug thereof. Compounds of the formula (II) and (III): 
     
       
         
         
             
             
         
       
     
     wherein ring A is an optionally substituted 5- to 7-membered ring; Q is C, CR 5  or N; R 8 , R 9 , R 10 , R 11  and R 12  are independently, H, an optionally substituted hydrocarbon group, etc., or a salt thereof are also provided. 
     Also specify X 1 , R 3 , R 1 , Y and X 3  in formula (II) and (III) as before.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to heterocyclic compounds havingcalcium-sensing receptor (CaSR, hereinafter simply referred to as Careceptor) modulating (agonistic or antagonistic) activity,pharmaceutical compositions containing them and intermediate compoundsuseful for synthesizing them.

2. Background Art

Calcium ion (hereinafter simply referred to as Ca) plays an essentialrole to maintain and modulate functions of various cells such asendocrine and exocrine cells, etc., in addition to nerve and muscle. Forthis reason, the blood Ca level is strictly maintained in a narrowrange. Parathyroid hormone (PTH) plays a central role in maintainingthis blood Ca level. Therefore, secretion of PTH from parathyroid glandresponds sharply to change in the blood Ca level and is must bemodulated according to this. In fact, when the blood Ca level ischanged, the blood PTH level is rapidly changed in response to this. Thepossibility of a mechanism by which the extracellular Ca concentrationis sensed by parathyroid gland cells and the information transmittedinto cells has been pointed out early by Brown et al. In 1993, theysucceeded in the cloning and characterization of a Ca-sensing receptor(CaSR; hereinafter, simply referred to as Ca receptor) from bovineparathyroid (Nature, 366, 575-580 (1993)).

The Ca receptor is composed of a large terminal extracellular regionspanning 600 amino acids at the N-terminal, having seven transmembranespanning domains like other G protein coupled receptors, and anintracellular region consisting of 200 or less amino acids at thecarboxyl C-terminal.

It is considered that, when the extracellular Ca concentration isincreased, phospholipase (PL)-C is activated, leading to increase in theintracellular Ca concentration and inhibition of PTH secretion due toincrease in inositol triphosphate (IP₃). Since when a high value of theextracellular Ca concentration is maintained, the intracellular Caconcentration is thereafter increased continuously, it is consideredthat influx of Ca from the outside of a cell is also promoted. PL-A₂ andD are activated due to increase in extracellular Ca, but there is apossibility that these are via protein kinase (PK)-C and the like whichare activated at the same time via Ca receptor. The Ca receptor alsoinhibits adenylyl cyclase via Gi protein or via arachidonic acidproduction due to activation of PL-A₂ and decreases intracellular cyclicAMP (Bone, 20, 303-309 (1997)).

Ca receptor mRNA is expressed in many tissues, and the expression amountis high, in parathyroid gland, thyroid gland C cell, medulla and cortexthick ascending limb (MTAL and CTAL) of kidney uriniferous tubule,intramedullary collecting tubule (IMCD) and encephalic subformical organ(SFO) and hippocampus (Bone, 20, 303-309 (1997)). In addition,expression is recognized in many tissues such as encephalichypothalamus, cerebellum and olfactory nucleus, regions other than TALof renal uriniferous tubule, lung, stomach, pancreas, intestine andskin. Since the Ca receptor is present in various tissues, itsphysiological function has yet to be fully understood. However, it isexpected that the Ca receptor modulating (agonistic or antagonistic)drug would provide for a novel treatment of various disease states whichinclude the following:

1. Drugs for Treating Bone Diseases

Since the anabolic activity is manifested by intermittent administrationof PTH, Ca receptor modulating drugs which are considered to be able toregulate secretion of PTH are promising as a drug for treatingosteoporosis. In addition, Ca receptor modulating drugs which areselectable for thyroid gland C cell may be also effective for treatingosteoporosis by stimulation of calcitonin secretion. Whether the same Careceptor as that of parathyroid gland is present in osteoblast,osteoclast and bone cell or not is disputable. However, some Ca-sensingmechanism is assuredly present therein and, therefore, drugs whichdirectly act on them can be expected as a drug for treating bonediseases.

2. Kidney-Acting Drugs

Handling of water and mineral in kidney is not only based on the resultsof function as a target organ for hormones, such as PTH, vitamin D etc.,but also the Ca receptor in kidney is presumed to function in a responseto the Ca concentration and the magnesium ion concentration in theextracellular fluid (Kidney Int, 50, 2129-2139 (1996)). Further, it isalso considered that Ca receptor modulating drugs may modulate the bloodamount in kidney, the amount of glomerulus filtration, rennin secretionand activation of vitamin D in addition to control of influx and effluxof water and mineral.

3. Central Nervous System and Endocrine-Acting Drugs

Ca receptor is present in almost all areas in the central nervoussystem, and is remarkably expressed, in particular, in the hippocampus,cerebellum and subformical organ (Brain Res, 744. 47-56 (1997)).Although the details of the function are still unclear, the term of Careceptor expression after birth in the hippocampus is consistent withthe term of acquisition of LTP (Long Tightening Phenomenon) (DevelopBrain Res, 100, 13-21 (1997)) and, therefore, the relationship withmemory and learning can be presumed. Therefore, Ca receptor modulatingdrugs which are high in brain-blood barrier permeability and selectivefor the central nerve system may be utilized for treating Alzheimer'sdisease. In addition, since dry mouth occurs in hypercalcemic patient,Ca receptor modulating drugs may control them. The presence of Careceptor in mouse pituitary gland cells which secreteACTH has beenreported (Mol Endocrinol, 10, 555-565 (1996)). It is also consideredthat Ca receptor modulating drugs can be applied to Sheehann's syndromeand hypopituitarism or hyperpituitarism.

4. Digestive System-Acting Drugs

It is considered that a Ca receptor is present in the Auerbach nerveplexus of the digestive tract and controls intestinal tract motion.Constipation is known in hypercalcemic patients and stimulation ofdigestive tract motion is known in hypocalcemic patients in clinicaltests. The existence of a Ca receptor in the gastrin secreting cell (Gcell) of the stomach has been reported (J. Clin Invest, 99, 2328-2333(1997)), and intestinal tract absorption, constipation, diarrhea,defecation and secretion of acid in the stomach may be controlled bydrugs which act on a Ca receptor in the digestive tract. Further, it hasbeen found that a Ca receptor is present in human colon cancer cellstrains and it controls c-myc expression and proliferation (BiochemBiophys Res Commum, 232, 80-83 (1997)), this is better consistent withthe fact that the Ca uptake and sideration of colon and rectum cancersexhibit the negative correlation and, therefore, Ca receptor regulatingdrugs can be expected also as a drug for preventing and treating suchcancers.

Various heterocyclic compounds have been disclosed in the prior art. Forexample, WO 01/53266 discloses a compound of the formula:

where in R, R¹ and R² are independently H, hydroxyl, etc. This compoundhas a phosphoinositide 3-kinase inhibitory activity and is useful fortreating coronary obstruction, etc. Indian J. Chem., Sect. B (1993),32B(5), 586-9 discloses the synthesis of a compound of the formula:

wherein R is hydrogen, chlorine, methyl or methoxy. However, no utilityis disclosed. U.S. Pat. No. 4,746,656 (JP 63-33380 A) discloses acompound of the formula:

wherein R₁ is aryl or heterocyclic group, R₂ is aryl, etc., R₃ and R₄are independently H, alkyl, etc. This compound is a Ca channel blocker.EP 217142 discloses a compound of the formula:

wherein R is hydrogen, alkyl, etc., R₁ is hydrogen, nitro, cyano, etc.,R₂ is phenyl, cycloalkyl, etc., R₃ is hydrogen, acyl etc., and R₈ iscarboxyl, carbamoyl, etc. This compound is also a Ca channel blocker.

However, a heterocyclic compound having Ca receptor modulating activityis not found in the prior art.

OBJECTS OF THE INVENTION

One object of the present invention is to provide compounds having Careceptor modulating activity including novel compounds.

Another object of the present invention is to provide pharmaceuticalcompositions containing the compounds of the present invention.

These objects as well as other objects and advantages of the presentinvention will become apparent to those skilled in the art from thefollowing description.

SUMMARY OF THE INVENTION

The present inventors have intensively investigated compounds having Careceptor modulating activity. As a result, it has been found thatcompounds represented by formula (I) as shown hereinafter have Careceptor modulating activity useful for medicine and, among them,compounds represented by the formulas (II), (III) and (IIIa) as shownhereinafter are novel compounds.

According to the present invention, there is provided:

1. A compound of the formula (II):

wherein ring A is an optionally substituted 5- to 7-membered ring;

Q is C, CR⁵ (wherein R⁵ is H, an optionally substituted hydrocarbongroup, an optionally substituted hydroxyl group, an optionallysubstituted amino group, an optionally substituted thiol group, cyanogroup, a halogen atom, an optionally substituted heterocyclic group, ora group of the formula: -Z¹-Z² (wherein -Z¹- is —CO—, —CS—, —SO— or—SO₂—, and Z² is an optionally substituted hydrocarbon group, anoptionally substituted heterocyclic group, an optionally substitutedhydroxyl group, or an optionally substituted amino group)), or N;

X¹ is CR¹ (wherein R¹ is H, an optionally substituted hydrocarbon group,an optionally substituted hydroxyl group, an optionally substitutedamino group, an optionally substituted thiol group, cyano group, ahalogen atom, an optionally substituted heterocyclic group, or a groupof the formula: -Z¹-Z² (wherein -Z¹- and Z² are as defined above)),CR¹R² (wherein R¹ is as defined above, and R² is H, or an optionallysubstituted hydrocarbon group), N, or NR¹³ (wherein R¹³ is H, anoptionally substituted hydrocarbon group, an optionally substitutedhydroxyl group, an optionally substituted amino group, an optionallysubstituted heterocyclic group, or a group of the formula: -Z¹-Z²(wherein -Z¹- and Z² are as defined above));

R³ is H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- and Z² are as defined above);

Y is C, CR⁴ (wherein R⁴ is H, an optionally substituted hydrocarbongroup, an optionally substituted hydroxyl group, an optionallysubstituted amino group, an optionally substituted thiol group, cyanogroup, a halogen atom, an optionally substituted heterocyclic group, ora group of the formula: -Z¹-Z² (wherein -Z¹- and Z² are as definedabove)), or N;

Ar is an optionally substituted cyclic group;

R⁹ and R¹⁰ are the same or different and are H, an optionallysubstituted hydrocarbon group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substituted thiolgroup, cyano group, a halogen atom, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above); and R¹¹ and R¹² are the same or different andare H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, cyano group, a halogen atom, anoptionally substituted heterocyclic group, or a group of the formula:-Z^(1′)-Z² (wherein -Z^(1′)- is —CS—, —SO— or —SO₂—, and Z² is asdefined above); or R⁹ and R¹⁰, or R¹¹ and R¹² may be combined to form anoxo group, methylene group or a ring; or R¹⁰ and R¹¹ may be combined toform a ring; and

is a single bond or a double bond;

provided that

(1) when ring A is a 6-membered ring and Q is C or CR⁵, X¹ is C-Z¹-Z²,C(-Z¹-Z²)R² or N-Z¹-Z², and both R⁹ and R¹⁰ are not H, or R⁹ and R¹⁰ arenot combined to form an oxo group, or R¹⁰ and R¹¹ are not combined toform a 5-membered ring,

(2) when ring A is a 6-membered ring and Q is N, X¹ is C-Z¹-Z²,C(-Z¹-Z²)R² or N-Z¹-Z², and R⁹ and R¹⁰ are not combined to form an oxogroup,

(3) when ring A is a 5-membered ring and Q is C or CR⁵, X¹ is C-Z¹-Z²,C(-Z¹-Z²)R² or N-Z¹-Z², and Z² is an optionally substituted amino group,and

(4) when ring A is a 5-membered ring and Q is N, at least one of R⁹ andR¹⁰ is CHR¹⁵R¹⁶ (wherein at least one of R¹⁵ and R¹⁶ are the same ordifferent and are H, an optionally substituted hydrocarbon group, anoptionally substituted hydroxyl group, an optionally substituted aminogroup, an optionally substituted thiol group, a halogen atom, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- and Z² are as defined above)) and the other isother than an optionally substituted phenyl group; or a salt thereof;

2. A compound of the formula (III):

wherein R¹ is H, an optionally substituted hydrocarbon group, anoptionally substituted hydroxyl group, an optionally substituted thiolgroup, an optionally substituted amino group, cyano group, a halogenatom, an optionally substituted heterocyclic group, or a group of theformula: -Z¹-Z² (wherein -Z¹- is —CO—, —CS—, —SO— or —SO₂—, and Z² is anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group, an optionally substituted hydroxyl group, or anoptionally substituted amino group);

R³ is H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- and Z² are as defined above);

Y is C, CR⁴ (wherein R⁴ is H, an optionally substituted hydrocarbongroup, an optionally substituted hydroxyl group, an optionallysubstituted amino group, an optionally substituted thiol group, cyanogroup, a halogen atom, an optionally substituted heterocyclic group, ora group of the formula: -Z¹-Z² (wherein -Z¹- and Z² are as definedabove)) or N;

R⁸ is H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, cyano group, a halogen atom, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- and Z² are as defined above);

Ar is an optionally substituted cyclic group;

R⁹ and R¹⁰ are the same or different and are H, an optionallysubstituted hydrocarbon group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substituted thiolgroup, cyano group, a halogen atom, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above), or R⁹ and R¹⁰ may be combined to form an oxogroup, methylene group or a ring;

X³ is a bond, oxygen atom, an optionally oxidized sulfur atom, N,NR^(7′) (wherein R^(7′) is H, an optionally substituted hydrocarbongroup, an optionally substituted hydroxyl group, an optionallysubstituted amino group, an optionally substituted heterocyclic group,or a group of the formula -Z^(1′)-Z² (wherein -Z^(1′)- is —CS—, —SO— or—SO₂—, and Z² is as defined above)), or an optionally substitutedbivalent C₁₋₂ hydrocarbon group; and

is a single bond or a double bond;

provided that at least one of R⁹ and R¹⁰ is CHR¹⁵R¹⁶ (wherein R¹⁵ andR¹⁶ are the same or different and are H, an optionally substitutedhydrocarbon group, an optionally substituted hydroxyl group, anoptionally substituted amino group, an optionally substituted thiolgroup, a halogen atom, an optionally substituted heterocyclic group, ora group of the formula: -Z¹-Z² (wherein -Z¹- and Z² are as definedabove)) and the other is other than an optionally substituted phenylgroup; or a salt thereof;

3. The compound according to the above 1 or 2, wherein R¹ is (1) anoptionally substituted heterocyclic group, or (2) a group of theformula: -Z¹-Z² (wherein -Z¹- is —CO—, —CS—, —SO— or —SO₂—, and Z² is anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group, an optionally substituted hydroxyl group, or anoptionally substituted amino group);

4. The compound according to the above 3, wherein Z¹ is —CO— and Z² isan optionally substituted hydroxyl group or an optionally substitutedamino group;

5. The compound according to the above 2, wherein R³ is H, a C₁₋₆ alkylgroup or a C₇₋₁₄ aralkyl group;

6. The compound according to the above 2, wherein R⁸ is H, a C₁₋₆ alkylgroup, a C₁₋₆ alkylthio group or a C₁₋₆ alkoxy group which may besubstituted with hydroxyl group;

7. The compound according to the above 1 or 2, wherein R⁹ and R¹⁰ arethe same or different and are a C₁₋₆ alkyl group or R⁹ and R¹⁰ arecombined each other to form a ring;

8. The compound according to the above 2, wherein R¹ is a group of theformula: -Z¹-Z² (wherein -Z¹- is —CO—, —CS—, —SO— or —SO₂—, and Z² is anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group, an optionally substituted hydroxyl group, or anoptionally substituted amino group); R³ is H; Ar is an optionallysubstituted aromatic ring group; X³ is CR¹¹R¹² (wherein R¹¹ and R¹² arethe same or different and are H, an optionally substituted hydrocarbongroup, an optionally substituted hydroxyl group, an optionallysubstituted amino group, an optionally substituted thiol group, cyanogroup, a halogen atom, an optionally substituted heterocyclic group, ora group of the formula: -Z¹-Z² (wherein -Z¹- and Z² are as definedabove), or R¹¹ and R¹² may be combined to form an oxo group, methylenegroup or a ring); and R⁹ and R¹⁰ are the same or different and a C₁₋₆alkyl group, or R⁹ and R¹⁰ may be combined to form a ring;

9. The compound according to the above 8, wherein R¹ is an optionallysubstituted carbamoyl group;

10. The compound according to the above 9, wherein R¹ is a group of theformula: —CONR²⁰(CR²¹R²²R²³) (wherein R²⁰ is H or an optionallysubstituted hydrocarbon group, and R²¹, R²², and R²³ are the same ordifferent and are an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, or R²⁰ and R²¹ may becombined to form a ring);

11. A compound of the formula (IIIa):

wherein R^(1a) is (1) an optionally substituted heterocyclic group, or(2) a group of the formula: -Z^(1a)-Z^(2a), (wherein -Z^(1a)- is —CO—,—CS—, —SO— or —SO₂—, and Z^(2a) is (i) an optionally substitutedheterocyclic group, (ii) —NR^(20a)(CR^(21a)R^(22a)R^(23a)) (wherein (a)R^(20a) is H or an optionally substituted hydrocarbon group; and R^(21a)is an optionally substituted heterocyclic group which may be fused withan optionally substituted benzene ring, or an optionally substitutedphenyl group which may be fused with an optionally substituted aromaticheterocyclic ring and R^(22a) and R^(23a) are the same or different andare an optionally substituted hydrocarbon group or an optionallysubstituted heterocyclic group or R^(22a) and R^(23a) may be combined toform a ring, or (b) R^(20a) is H or an optionally substitutedhydrocarbon group; and R^(21a), R^(22a) and R^(23a) are the same ordifferent and are an optionally substituted C₁₋₈ aliphatic hydrocarbongroup, provided that the sum total of the number of carbon atoms is 7 ormore), (iii) —NR^(20a)R^(25a) (wherein R^(20a) is as defined above andR^(25a) is an optionally substituted C₆₋₁₀ aryl-C₂₋₄ alkyl, C₆₋₁₀aryloxy-C₂₋₄ alkyl, C₆₋₁₀ arylamino-C₂₋₄ alkyl, C₇₋₁₄ aralkylamino-C₂₋₄alkyl, heterocyclic ring-C₂₋₄ alkyl or heterocyclic group), (iv) asubstituted 5- to 7-membered cyclic amino group, or (v) —OR^(24a)(wherein R^(24a) is (a) an optionally substituted C₇₋₁₄ aralkyl group,(b) an optionally substituted C₃₋₇ alicyclic hydrocarbon group, (c) anoptionally substituted C₇₋₂₄ aliphatic hydrocarbon group, or (d) anoptionally substituted heterocyclic group);

R³ is H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- is —CO—, —CS—, —SO— or —SO₂—, and Z² is anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group, an optionally substituted hydroxyl group, or anoptionally substituted amino group);

Y is C, CR⁴ (wherein R⁴ is H, an optionally substituted hydrocarbongroup, an optionally substituted hydroxyl group, an optionallysubstituted amino group, an optionally substituted thiol group, cyanogroup, a halogen atom, an optionally substituted heterocyclic group, ora group of the formula: -Z¹-Z² (wherein -Z¹- and Z² are as definedabove)) or N;

R⁸ is H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, cyano group, a halogen atom, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- and Z² are as defined above);

Ar is an optionally substituted cyclic group;

R⁹ and R¹⁰ are the same or different and are H, an optionallysubstituted hydrocarbon group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substituted thiolgroup, cyano group, a halogen atom, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above), or R⁹ and R¹⁰ may be combined to form an oxogroup, methylene group or a ring;

X³ is a bond, oxygen atom, an optionally oxidized sulfur atom, N,NR^(7′) (wherein R^(7′) is H, an optionally substituted hydrocarbongroup, an optionally substituted hydroxyl group, an optionallysubstituted amino group, an optionally substituted heterocyclic group,or a group of the formula -Z^(1′)-Z² (wherein -Z^(1′)- is —CS—, —SO— or—SO₂—, and Z² is as defined above)), or an optionally substitutedbivalent C₁₋₂ hydrocarbon group; and

is a single bond or a double bond;

provided that at least one of R⁹ and R¹⁰ is CHR¹⁵R¹⁶ (wherein R¹⁵ andR¹⁶ are the same or different and are H, an optionally substitutedhydrocarbon group, an optionally substituted hydroxyl group, anoptionally substituted amino group, an optionally substituted thiolgroup, a halogen atom, an optionally substituted heterocyclic group, ora group of the formula: -Z¹-Z² (wherein -Z¹- and Z² are as definedabove)) and the other is other than an optionally substituted phenylgroup; or a salt thereof;

12. The compound according to the above 11, wherein R^(1a) is a group ofthe formula: —CONR^(20a)(CR^(21b)R^(22b)R^(23b)) (wherein R^(20a) is asdefined above and at least one of R^(21b), R^(22b), and R^(23b) is anoptionally substituted heterocyclic group which may be fused with anoptionally substituted benzene ring, or an optionally substituted phenylgroup which may be fused with an optionally substituted aromaticheterocyclic ring);

13. The compound according to the above 11, wherein R^(1a) is (1) anoptionally substituted 5- to 7-membered aromatic or non-aromaticheterocyclic group having 1-4 hetero atoms selected from nitrogen atom,oxygen atom and sulfur atom, or (2) a group of the formula: —CO-Z^(2c)(wherein Z^(2c) is (i) an optionally substituted 5- to 7-memberedaromatic or non-aromatic heterocyclic group having 1-4 hetero atomsselected from nitrogen atom, oxygen atom and sulfur atom, (ii) —NR^(20c)(CR^(21c)R^(22c)R^(23c)) (wherein (a) R^(20c) is H or an optionallysubstituted hydrocarbon group selected from C₁₋₈ saturated aliphatichydrocarbon group, C₂₋₈ unsaturated aliphatic hydrocarbon group, C₃₋₇saturated alicyclic hydrocarbon group, C₃₋₇ unsaturated alicyclichydrocarbon group, C₉₋₁₀ partly saturated and fused bicyclic hydrocarbongroup, C₃₋₇ saturated or unsaturated alicyclic-C₁₋₈ saturated orunsaturated aliphatic hydrocarbon group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon-C₁₋₄ alkyl group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon-C₂₋₄ alkenyl group, C₆₋₁₀ aryl group andC₇₋₁₄ aralkyl group; and R^(21c) is 1) an optionally substituted 5- to7-membered aromatic or non-aromatic heterocyclic group having 1-4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, whichmay be fused with an optionally substituted benzene ring, or 2) anoptionally substituted C₆₋₁₀ aryl group which may be fused with anoptionally substituted 5- to 7-membered aromatic heterocyclic ringhaving 1-4 hetero atoms selected from nitrogen atom, oxygen atom andsulfur atom; and R^(22c) and R^(23c) are the same or different and arean optionally substituted hydrocarbon group selected from C₁₋₈ saturatedaliphatic hydrocarbon group, C₂₋₈ unsaturated aliphatic hydrocarbongroup, C₃₋₇ saturated alicyclic hydrocarbon group, C₃₋₇ unsaturatedalicyclic hydrocarbon group, C₉₋₁₀ partly saturated and fused bicyclichydrocarbon group, C₃₋₇ saturated or unsaturated alicyclic-C₁₋₈saturated or unsaturated aliphatic hydrocarbon group, C₉₋₁₀ partlysaturated and fused bicyclic hydrocarbon-C₁₋₄ alkyl group, C₉₋₁₀ partlysaturated and fused bicyclic hydrocarbon-C₂₋₄ alkenyl group, C₆₋₁₀ arylgroup and C₇₋₁₄ aralkyl group or an optionally substituted 5- to7-membered aromatic or non-aromatic heterocyclic group having 1-4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, orR^(22c) and R^(23c) may be combined to form a C₃₋₇ carbon ring, or

(b) R^(20c) is H or an optionally substituted hydrocarbon group selectedfrom C₁₋₈ saturated aliphatic hydrocarbon group, C₂₋₈ unsaturatedaliphatic hydrocarbon group, C₃₋₇ saturated alicyclic hydrocarbon group,C₃₋₇ unsaturated alicyclic hydrocarbon group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon group, C₃₋₇ saturated or unsaturatedalicyclic-C₁₋₈ saturated or unsaturated aliphatic hydrocarbon group,C₉₋₁₀ partly saturated and fused bicyclic hydrocarbon-C₁₋₄ alkyl group,C₉₋₁₀ partly saturated and fused bicyclic hydrocarbon-C₂₋₄ alkenylgroup, C₆₋₁₀ aryl group and C₇₋₁₄ aralkyl group; and R^(21c), R^(22c)and R^(23c) are the same or different and are an optionally substitutedC₁₋₈ aliphatic hydrocarbon group, provided that the sum total of thenumber of carbon atoms is 7 or more),

(iii) —NR^(20c)R^(25c) (wherein R^(20c) is as defined above and R^(25c)is an optionally substituted C₆₋₁₀ aryl-C₂₋₄ alkyl, C₆₋₁₀ aryloxy-C₂₋₄alkyl, C₆₋₁₀ arylamino-C₂₋₄ alkyl, C₇₋₁₄ aralkylamino-C₂₋₄ alkyl, 5- to7-membered heterocyclic ring (having 1-4 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom)-C₂₋₄ alkyl or 5- to7-membered heterocyclic group having 1-4 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom),

(iv) a substituted 5- to 7-membered cyclic amino group, or

(v) —OR^(24c) (wherein R^(24c) is (a) an optionally substituted C₇₋₁₄aralkyl group, (b) an optionally substituted C₃₋₇ alicyclic hydrocarbongroup, (c) an optionally substituted C₇₋₂₄ aliphatic hydrocarbon group,or (d) an optionally substituted 5- to 7-membered aromatic ornon-aromatic heterocyclic group having 1-4 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom;

wherein said substituents for R^(1a), Z^(2c), R^(20c), R^(21c), R^(22c),R^(23c), R^(24c) and R^(25c) are 1 to 3 substituents selected from thegroup consisting of

-   -   1) C₁₋₆ alkyl,    -   2) C₂₋₆ alkenyl,    -   3) C₂₋₆ alkynyl,    -   4) C₃₋₇ cycloalkyl,    -   5) C₆₋₁₀ aryl which may be substituted with 1 to 3 substituents        selected from the group consisting of C₁₋₆ alkyl, amino, N—(C₁₋₆        alkyl)amino, N,N-di-(C₁₋₆ alkyl)amino, amidino, carbamoyl,        N—(C₁₋₆ alkyl)carbamoyl, N,N-di-(C₁₋₆ alkyl)carbamoyl,        sulfamoyl, N—(C₁₋₆ alkyl)sulfamoyl, N,N-di-(C₁₋₆        alkyl)sulfamoyl, carboxyl, C₂₋₇ alkoxycarbonyl, hydroxyl, C₁₋₆        alkoxy, mercapto, C₁₋₆ alkylthio, sulfo, cyano, azido, halogen,        nitro, nitroso, phosphono, C₁₋₆ alkoxyphosphoryl, di-(C₁₋₆        alkoxy)phosphoryl and C₁₋₆ alkyl substituted with phosphono,        C₁₋₆ alkoxyphosphoryl and di-(C₁₋₆ alkoxy)phosphoryl        (hereinafter the group of 5) is referred to as group “C”),    -   6) aromatic heterocyclic group selected from (a) aromatic 5- or        6-membered heterocyclic group having 1-4 hetero atoms selected        from nitrogen atom, oxygen atom and sulfur atom, (b) fused        bicyclic heterocyclic group formed by condensation of an        aromatic 5- or 6-membered heterocyclic group having 1 to 3        hetero atoms selected from nitrogen atom, oxygen atom and sulfur        atom with benzene ring or an aromatic 5- or 6-membered        heterocyclic group having 1 to 3 hetero atoms selected from        nitrogen atom, oxygen atom and sulfur atom and (c) fused        tricyclic heterocyclic group formed by condensation of [1] an        aromatic 5- or 6-membered heterocyclic group having 1-3 hetero        atoms selected from nitrogen atom, oxygen atom and sulfur atom,        [2] benzene ring, and [3] an aromatic 5- or 6-membered        heterocyclic group having 1-3 hetero atoms selected from        nitrogen atom, oxygen atom and sulfur atom or benzene ring,    -   7) heterocyclic-oxy group formed by combining each of the above        aromatic heterocyclic groups (a), (b) and (c) with oxy group,    -   8) non-aromatic 4- or 7-membered heterocyclic group having 1 to        3 hetero atoms selected from nitrogen atom, oxygen atom and        sulfur atom,    -   9) C₇₋₁₄ aralkyl which may be substituted with 1 to 3        substituents selected from the group “C”,    -   10) amino group,    -   11) N-mono-substituted amino selected from N—(C₁₋₆ alkyl)amino,        N—(C₂₋₆ alkenyl)amino, N—(C₃₋₇ cycloalkyl)amino group and        N—(C₆₋₁₀ aryl)amino which may be substituted with 1 to 3        substituents selected from the group “C”,    -   12) amino substituted with two substituents selected from C₁₋₆        alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkenyl and C₆₋₁₀ aryl which may        be substituted with 1 to 3 substituents selected from the group        “C”,    -   13) amidino,    -   14) acyl selected from C₂₋₈ alkanoyl, C₃₋₈ alkenoyl, C₃₋₇        cycloalkyl-carbonyl, C₃₋₇ cycloalkenyl-carbonyl, C₆₋₁₀        aryl-carbonyl which may be substituted with 1 to 3 substituents        selected from the group “C”, and heterocyclic-carbonyl formed by        binding of an aromatic or non-aromatic 5- or 6-membered        heterocyclic group having 1-3 hetero atoms selected from        nitrogen atom, oxygen atom and sulfur atom with carbonyl,    -   15) carbamoyl,    -   16) mono-substituted carbamoyl group selected from N—(C₁₋₆        alkyl)carbamoyl, N—(C₂₋₆ alkenyl)carbamoyl, N—(C₃₋₇        cycloalkyl)carbamoyl and N—(C₆₋₁₀ aryl)carbamoyl which may be        substituted with 1 to 3 substituents selected from the group        “C”,    -   17) carbamoyl substituted with two substituents selected from        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl and C₆₋₁₀ aryl which        may be substituted with 1 to 3 substituents selected from the        group “C”,    -   18) sulfamoyl,    -   19) N-mono-substituted sulfamoyl selected from N—(C₁₋₆        alkyl)sulfamoyl, N—(C₂₋₆ alkenyl)sulfamoyl, N—(C₃₋₇        cycloalkyl)sulfamoyl and N—(C₆₋₁₀ aryl)sulfamoyl which may be        substituted with 1 to 3 substituents selected from the group        “C”,    -   20) sulfamoyl substituted with two substituents selected from        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl and C₆₋₁₀ aryl which        may be substituted with 1 to 3 substituents selected from the        group “C”,    -   21) carboxyl,    -   22) C₁₋₆ alkoxy-carbonyl,    -   23) hydroxyl,    -   24) C₁₋₆ alkoxy,    -   25) C₂₋₁₀ alkenyloxy,    -   26) C₃₋₇ cycloalkyloxy,    -   27) C₆₋₁₀ aryloxy which may be substituted with 1 to 3        substituents selected from the group “C”,    -   28) C₇₋₁₄ aralkyloxy which may be substituted with 1 to 3        substituents selected from the group “C”,    -   29) mercapto,    -   30) C₁₋₆ alkylthio,    -   31) C₇₋₁₄ aralkylthio which may be substituted with 1 to 3        substituents selected from the group “C”,    -   32) C₆₋₁₀ arylthio which may be substituted with 1 to 3        substituents selected from the group “C”,    -   33) C₁₋₆ alkylsulfinyl,    -   34) C₇₋₁₄ aralkylsulfinyl which may be substituted with 1 to 3        substituents selected from the group “C”,    -   35) C₆₋₁₀ arylsulfinyl which may be substituted with 1 to 3        substituents selected from the group “C”,    -   36) C₁₋₆ alkylsulfonyl,    -   38) C₇₋₁₄ aralkylsulfonyl which may be substituted with 1 to 3        substituents selected from the group “C”,    -   39) C₆₋₁₀ arylsulfonyl which may be substituted with 1 to 3        substituents selected from the group “C”,    -   40) sulfo,    -   41) cyano,    -   42) azido,    -   43) halogen,    -   44) nitro,    -   45) nitroso,    -   46) phosphono,    -   47) C₁₋₆ alkoxy-phosphoryl    -   48) di-C₁₋₆ alkoxy-phosphoryl,    -   49) C₁₋₆ alkyl substituted with phosphono, C₁₋₆ alkoxyphosphoryl        or di-(C₁₋₆ alkoxy)phosphoryl    -   50) C₁₋₆ alkyl substituted with 1 to 4 halogen atoms    -   51) C₁₋₆ alkoxy substituted with 1 to 4 halogen atoms and    -   52) C₁₋₆ alkylenedioxy (hereinafter the group of above 1) to 52)        is referred to as group “B”);

R³ is H, a C₁₋₆ alkyl group or a C₇₋₁₄ aralkyl group;

Y is CH;

R⁸ is H, a C₁₋₆ alkyl group, a C₁₋₆ alkylthio group or a C₁₋₆ alkoxygroup which may be substituted with hydroxyl group; Ar is (1) a C₆₋₁₀aryl group, (2) a 5- to 7-membered aromatic or non-aromatic heterocyclicgroup having 1-4 hetero atoms selected from nitrogen atom, oxygen atomand sulfur atom, or (3) a C₃₋₇ saturated or unsaturated alicyclichydrocarbon group, each of which may be substituted with 1 to 3substituents selected from the group “B”;

one of R⁹ and R¹⁰ is a hydrogen atom or C₁₋₆ alkyl group which may besubstituted with 1 to 3 substituents selected from the group “B” and theother is (1) a hydrocarbon group selected from C₁₋₈ saturated aliphatichydrocarbon group, C₂₋₈ unsaturated aliphatic hydrocarbon group, C₃₋₇saturated alicyclic hydrocarbon group, C₃₋₇ unsaturated alicyclichydrocarbon group, C₉₋₁₀ partly saturated and fused bicyclic hydrocarbongroup, C₃₋₇ saturated or unsaturated alicyclic-C₁₋₈ saturated orunsaturated aliphatic hydrocarbon group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon-C₁₋₄ alkyl group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon-C₂₋₄ alkenyl group, C₆₋₁₀ aryl group andC₇₋₁₄ aralkyl group, each of which may be substituted with 1 to 3substituents selected from the group “B” or (2) a 5- to 7-memberedaromatic or non-aromatic heterocyclic group having 1-4 hetero atomsselected from nitrogen atom, oxygen atom and sulfur atom, which may besubstituted with 1 to 3 substituents selected from the group “B”, or

R⁹ and R¹⁰ may be combined to form a C₅₋₇ carbon ring; and X³ is CH₂;

14. The compound according to the above 8, wherein R¹ is a group of theformula: —CONR²⁰(CR²¹R²²R²³) (wherein R²⁰ is H, and R²¹, R²², and R²³are the same or different and are an optionally substituted hydrocarbongroup or an optionally substituted heterocyclic group); R³ is H; Ar isan optionally substituted aromatic ring group; X³ is CH₂; Y is CH; R⁸ isH or an optionally substituted hydrocarbon group, an optionallysubstituted alkoxy group, an optionally substituted sulfanyl group, anoptionally substituted sulfinyl group, or an optionally substitutedsulfonyl group, C₁₋₆ alkoxy-carbonyl; and R⁹ and R¹⁰ are the same ordifferent and are an optionally substituted hydrocarbon group;

15. The compound according to the above 14, wherein at least one of R²¹,R²², and R²³ is an optionally substituted heterocyclic group or anoptionally substituted phenyl group;

16. The compound according to the above 14, wherein R²⁰ and R²¹ arecombined to form an optionally substituted 5- to 7-membered ring, andR²² and R²³ are the same or different and are an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, or anoptionally substituted phenyl group;

17. The compound according to the above 14, wherein R²¹ and R²² are thesame or different and are a C₁₋₈ hydrocarbon group, and R²³ is anoptionally substituted 5-membered heterocyclic group which may be fusedwith an optionally substituted benzene ring, or an optionallysubstituted phenyl group;

18. The compound according to the above 16, wherein R²⁰ and R²¹ arecombined to form a 5- or 6-membered ring which may be fused with benzenering and/or substituted with 1 to 3 substituents selected from the groupconsisting of (1) halogen, (2) hydrogen, (3) a phenoxy which may besubstituted with 1 to 3 substituents selected from halogen, hydroxyl,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl, cyano, amino, mono-C₁₋₆ alkyl-amino,di-C₁₋₆ alkyl-amino, C₁₋₆ alkyl-sulfanyl, C₁₋₆ alkyl-sulfinyl, C₁₋₆alkyl-sulfonyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, N—C₁₋₆ alkyl-carbamoyland N,N-di-C₁₋₆ alkyl-carbamoyl,

(4) C₁₋₆ alkoxy which may be substituted with 1 to 3 substituentsselected from halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl,cyano, amino, mono-C₁₋₆ alkyl-amino, di-C₁₋₆ alkyl-amino, C₁₋₆alkyl-sulfanyl, C₁₋₆ alkyl-sulfinyl, C₁₋₆ alkyl-sulfonyl, C₁₋₆alkoxy-carbonyl, carbamoyl, N—C₁₋₆ alkyl-carbamoyl, N,N-di-C₁₋₆alkyl-carbamoyl and phenyl which may be substituted with 1 to 3substituents selected from halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ acyl, cyano, halogeno C₁₋₆ alkyl, amino, mono-C₁₋₆ alkyl-amino,di-C₁₋₆ alkyl-amino, C₁₋₆ alkyl-sulfanyl, C₁₋₆ alkyl-sulfinyl, C₁₋₆alkyl-sulfonyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, N—C₁₋₆ alkyl-carbamoyland N,N-di-C₁₋₆ alkyl-carbamoyl, and (5) a C₁₋₈ hydrocarbon group whichmay be substituted with 1 to 3 substituents selected from halogen,hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl, cyano, amino, mono-C₁₋₆alkyl-amino, di-C₁₋₆ alkyl-amino, C₁₋₆ alkyl-sulfanyl, C₁₋₆alkyl-sulfinyl, C₁₋₆ alkyl-sulfonyl, C₁₋₆ alkoxy-carbonyl, carbamoyl,N—C₁₋₆ alkyl-carbamoyl, N,N-di-C₁₋₆ alkyl-carbamoyl and phenyl which maybe substituted with 1 to 3 substituents selected from halogen, hydroxyl,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl, cyano, halogeno C₁₋₆ alkyl, amino,mono-C₁₋₆ alkyl-amino, di-C₁₋₆ alkyl-amino, C₁₋₆ alkyl-sulfanyl, C₁₋₆alkyl-sulfinyl, C₁₋₆ alkyl-sulfonyl, C₁₋₆ alkoxy-carbonyl, carbamoyl,N—C₁₋₆ alkyl-carbamoyl and N,N-di-C₁₋₆ alkyl-carbamoyl,

and R²² and R²³ are the same or different and C₁₋₈ hydrocarbon groupwhich may be substituted with 1 to 3 substituents selected from halogen,hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl, cyano, amino, mono-C₁₋₆alkyl-amino, di-C₁₋₆ alkyl-amino, C₁₋₆ alkyl-sulfanyl, C₁₋₆alkyl-sulfinyl, C₁₋₆ alkyl-sulfonyl, C₁₋₆ alkoxy-carbonyl, carbamoyl,N—C₁₋₆ alkyl-carbamoyl, N,N-di-C₁₋₆ alkyl-carbamoyl and phenyl which maybe substituted with 1 to 3 substituents selected from halogen, hydroxyl,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl, cyano, halogeno C₁₋₆ alkyl, amino,mono-C₁₋₆ alkyl-amino, di-C₁₋₆ alkyl-amino, C₁₋₆ alkyl-sulfanyl, C₁₋₆alkyl-sulfinyl, C₁₋₆ alkyl-sulfonyl, C₁₋₆ alkoxy-carbonyl, carbamoyl,N—C₁₋₆ alkyl-carbamoyl and N,N-di-C₁₋₆ alkyl-carbamoyl;

19.N-(1-ethyl-1-(4-methylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamideor a salt thereof,

-   N-(1-ethyl-1-(4-methylphenyl)propyl)-5-(2-fluorophenyl)-7,7-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide    or a salt thereof,-   N-(1-ethyl-1-(4-methylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide    or a salt thereof,-   N-(1-ethyl-1-(4-ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide    or a salt thereof,-   N-(1-ethyl-1-(4-methylphenyl)propyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide    or a salt thereof,-   N-(1-ethyl-1-(4-ethylphenyl)propyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide    or a salt thereof,-   5-(2-chlorophenyl)-N-(1-ethyl-1-(4-methylphenyl)propyl)-2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide    or a salt thereof,-   N-(1-(4-(dimethylamino)phenyl)-1-ethylpropyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide    or a salt thereof,-   N-(1,1-diethylbutyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide    or a salt thereof,-   N-(1-ethyl-1-phenylpropyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide    or a salt thereof,-   3-(5-(1-ethyl-1-(4-methylphenyl)propyl)-1,3,4-oxadiazol-2-yl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine    or a salt thereof,-   3-(5-(1-ethyl-1-(4-methylphenyl)propyl)-1,3,4-thiadiazol-2-yl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine    or a salt thereof,-   3-((4-(benzyloxy)-2,2-diethyl-1-pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine    or a salt thereof,-   3-((2,2-diethyl-4-methoxy-1-pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine    or a salt thereof, or-   3-((2,2-diethyl-4-fluoro-1-pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine    or a salt thereof;

20. The compound according to the above 19, which is an optically activecompound;

21. A prodrug of the compound according to the above 1, 2 or 13;

22. A pharmaceutical composition which comprises the compound accordingto the above 1, 2 or 13 or a prodrug thereof;

23. A composition for modulating calcium receptor which comprises acompound of the formula (I):

wherein ring A is an optionally substituted 5- to 7-membered ring;

ring B is an optionally substituted 5- to 7-membered heterocyclic ring;

X¹ is CR¹ (wherein R¹ is H, an optionally substituted hydrocarbon group,an optionally substituted hydroxyl group, an optionally substitutedamino group, an optionally substituted thiol group, cyano group, ahalogen atom, an optionally substituted heterocyclic group, or a groupof the formula: -Z¹-Z² (wherein -Z¹- is —CO—, —CS—, —SO— or —SO₂—, andZ² is an optionally substituted hydrocarbon group, an optionallysubstituted heterocyclic group, an optionally substituted hydroxylgroup, or an optionally substituted amino group)), CR¹R² (wherein R¹ isas defined above, R² is H or an optionally substituted hydrocarbongroup), N or NR¹³ (wherein R¹³ is H, an optionally substitutedhydrocarbon group, an optionally substituted hydroxyl group, anoptionally substituted amino group, cyano group, a halogen atom, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- and Z² are as defined above));

X² is N or NR³ (wherein R³ is H, an optionally substituted hydrocarbongroup, an optionally substituted hydroxyl group, an optionallysubstituted amino group, cyano group, a halogen atom, an optionallysubstituted heterocyclic group, or a group of the formula: -Z¹-Z²(wherein -Z¹- and Z² are as defined above);

Y is C, CR⁴ (wherein R⁴ is H, an optionally substituted hydrocarbongroup, an optionally substituted hydroxyl group, an optionallysubstituted amino group, an optionally substituted thiol group, cyanogroup, a halogen atom, an optionally substituted heterocyclic group, ora group of the formula: -Z¹-Z² (wherein -Z¹- and Z² are as definedabove)) or N;

Z is CR⁵ (wherein R⁵ is H, an optionally substituted hydrocarbon group,an optionally substituted hydroxyl group, an optionally substitutedamino group, an optionally substituted thiol group, cyano group, ahalogen atom, an optionally substituted heterocyclic group, or a groupof the formula: -Z¹-Z² (wherein -Z¹- and Z² are as defined above)),CR⁵R⁶ (wherein R⁵ and R⁶ are the same or different and are H, anoptionally substituted hydrocarbon group, an optionally substitutedhydroxyl group, an optionally substituted amino group, an optionallysubstituted thiol group, cyano group, a halogen atom, an optionallysubstituted heterocyclic group, or a group of the formula: -Z¹-Z²(wherein -Z¹- and Z² are as defined above)), N or NR⁷ (wherein R⁷ is H,an optionally substituted hydrocarbon group, an optionally substitutedhydroxyl group, an optionally substituted amino group, cyano group, ahalogen atom, an optionally substituted heterocyclic group, or a groupof the formula: -Z¹-Z² (wherein -Z¹- and Z² are as defined above));

Ar is an optionally substituted cyclic group;

R is H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, an optionally substituted sulfonylgroup or an optionally substituted sulfinyl group, or R and Z may becombined to form a ring B; and

is a single bond or a double bond;

or a salt thereof or a prodrug thereof;

24. The composition according to the above 23, which is a calciumreceptor antagonist;

25. The composition according to the above 23, which is an agent forpreventing or treating diseases caused by abnormality of calciumconcentration in a living body or a calcium receptor;

26. The composition according to the above 23, which is an agent forpreventing or treating bone diseases;

27. The composition according to the above 23, which is an agent forpreventing or treating osteoporosis or fracture;

28. A method for modulating a calcium receptor which comprisesadministering to a mammal an effective amount of a compound of theformula (I) or a salt thereof or a prodrug thereof according to theabove 23;

29. A method for preventing or treating bone diseases, which comprisesadministering to a mammal an effective amount of a compound of theformula (I) or a salt thereof or a prodrug thereof according to theabove 23;

30. Use of the compound of the formula (I) or a salt thereof or aprodrug thereof according to the above 23 for producing a calciumreceptor modulator; and

31. Use of the compound of the formula (I) or a salt thereof or aprodrug thereof according to the above 23 for producing a compositionfor preventing or treating bone diseases.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The above formula (I) includes a monocyclic heterocyclic compoundcontaining ring A and a condensed heterocyclic compound containing ringsA and B.

In the above formulas, ring A of the formulas (I) and (II) is anoptionally substituted 5- to 7-membered ring.

Examples of the “5- to 7-membered ring” of “an optionally substituted 5-to 7-membered ring” includes an aromatic or non-aromatic 5- to7-membered hydrocarbon ring or 5- to 7-membered heterocyclic ring whichmay contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfuratoms as the ring constituting atoms in addition to carbon atoms.Specific examples thereof include a hydrocarbon ring such as benzene,tropilidene, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentene,2-cyclopentene, 3-cyclopentene, 1-cyclohexene, 2-cyclohexene,3-cyclohexene, 1-cycloheptene, 2-cycloheptene, 3-cycloheptene,2,4-cycloheptadiene, etc.; a heterocyclic ring such as pyridine,pyrazine, pyrimidine, imidazole, furan, thiophene, dihydropyridine,diazepine, oxazepine, pyrrolidine, piperidine, hexamethyleneimine,heptamethyleneimine, tetrahydrofuran, piperazine, homopiperazine,tetrahydroxazepine, morpholine, thiomorpholine, pyrrole, pyrazole,1,2,3-triazole, oxazole, oxazolidine, thiazole, thiazolidine, isoxazole,imidazoline, triazole, thiadiazole, oxadiazole, oxathiadiazole,triazine, etc.; and the like.

Examples of the substituent(s) of “an optionally substituted 5- to7-membered ring group” include halogen, nitro, cyano, oxo, an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup, an optionally substituted sulfinyl group, an optionallysubstituted sulfonyl group, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally substituted aminogroup, an optionally substituted acyl group, an optionally esterified oramidated carboxyl group, an optionally substituted phosphoryl group, orthe like.

Examples of halogen include fluorine, chlorine, bromine, iodine, and thelike, preferably, fluorine and chlorine.

Examples of the hydrocarbon group in an optionally substitutedhydrocarbon group as the substituent of the 5- to 7-membered ring groupinclude an optionally substituted aliphatic hydrocarbon group, anoptionally substituted alicyclic hydrocarbon group, an optionallysubstituted alicyclic-aliphatic hydrocarbon group, an optionallysubstituted aromatic hydrocarbon group, an optionally substitutedaromatic-aliphatic hydrocarbon group (an aralkyl group), and the like.

Examples of said aliphatic hydrocarbon group include a saturatedaliphatic hydrocarbon group having 1-8 carbon atoms (e.g., alkyl group)such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl,heptyl, octyl, etc.; and an unsaturated aliphatic hydrocarbon grouphaving 2-8 carbon atoms (e.g., alkenyl group, alkynyl group, alkadienylgroup, alkadienyl group, etc.) such as vinyl, allyl, 1-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 2,4-hexadienyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl, 2,4-hexadienyl, 1-heptynyl, 1-octynyl, etc.

Examples of said alicyclic hydrocarbon group include a saturatedalicyclic hydrocarbon group having 3-7 carbon atoms (e.g., cycloalkylgroup, etc.) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and the like; an unsaturated alicyclic hydrocarbon grouphaving 3-7 carbon atoms (e.g., cycloalkenyl group, cycloalkadienylgroup, etc.) such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl,1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl,2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl, etc.; a partlysaturated and fused bicyclic hydrocarbon group [preferably, C₉₋₁₀ partlysaturated and fused bicyclic hydrocarbon group, etc. (including thosewhere the benzene ring is combined to 5- or 6-membered non-aromaticcyclic hydrocarbon group)] such as 1-indenyl, 2-indenyl, 1-indanyl,2-indanyl, 1,2,3,4-tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl,1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1-naphthyl,1,4-dihydro-2-naphthyl, 3,4-dihydro-1-naphthyl, 3,4-dihydro-2-naphthyl,etc.; and the like. Said alicyclic hydrocarbon group may becross-linked.

Examples of said alicyclic-aliphatic hydrocarbon group include thosewhere the above-mentioned alicyclic hydrocarbon group and theabove-mentioned aliphatic hydrocarbon group are combined, for example,those having 4-14 carbon atoms such as cyclopropylmethyl,cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl,2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclopentylethyl,cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl,cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl,2-(3,4-dihydro-2-naphtyl)ethyl, 2-(1,2,3,4-tetrahydro-2-naphtyl)ethyl,2-(3,4-dihydro-2-naphtyl)ethenyl, etc. (e.g., C₃₋₇ cycloalkyl-C₁₋₄ alkylgroup, C₃₋₇ cycloalkenyl-C₁₋₄ alkyl group, C₃₋₇ cycloalkyl-C₂₋₄ alkenylgroup, C₃₋₇ cycloalkenyl-C₂₋₄ alkenyl group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon-C₁₋₄ alkyl group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon-C₂₋₄ alkenyl groups, etc.).

Examples of said aromatic hydrocarbon group include an aryl group having6-10 carbon atoms (including that where a 5- to 6-membered non-aromatichydrocarbon ring is fused with phenyl group) such as phenyl, α-naphthyl,β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl,5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl,5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl,5,6-dihydro-4-naphthyl, etc.; and the like.

Examples of said aromatic-aliphatic hydrocarbon group include an aralkylgroup having 7-14 carbon atoms (C₆₋₁₀ aryl-C₁₋₄ alkyl group) such asphenyl-C₁₋₄ alkyl group, e.g., benzyl, phenethyl, 1-phenylethyl,1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, etc.; naphthyl-C₁₋₄alkyl group such as α-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl,β-naphthylethyl, etc.; C₆₋₁₀ aryl-C₂₋₄ alkenyl group such as phenyl-C₂₋₄alkenyl group, e.g., styryl, cinnamyl, etc.; and the like.

Examples of the heterocyclic group in an optionally substitutedheterocyclic group as the substituent of the 5- to 7-membered ringinclude (i) a 5- to 7-membered heterocyclic group containing one sulfuratom, one nitrogen atom, or one oxygen atom, (ii) a 5- to 6-memberedheterocyclic group containing 2-4 nitrogen atoms, (iii) a 5- to6-membered heterocyclic group containing 1-2 nitrogen atoms and onesulfur or oxygen atom, or the like; and (iv) these heterocyclic groupsmay be fused with a 5- to 6-membered ring containing 2 or less nitrogenatoms, benzene ring, or a 5-membered ring containing one sulfur atom. Inaddition, each of the heterocyclic groups exemplified in (i) to (iv) maybe a saturated or unsaturated heterocyclic group and the unsaturatedheterocyclic group may be either aromatic or non-aromatic.

Examples of the heterocyclic group in an optionally substitutedheterocyclic group as the substituent of the 5- to 7-membered ringinclude an aromatic monocyclic heterocyclic group, an aromatic fusedheterocyclic group, and a non-aromatic heterocyclic group.

Specific examples of the heterocyclic group in an optionally substitutedheterocyclic group as the substituent of the 5- to 7-membered ringinclude (i) an aromatic monocyclic heterocyclic group (e.g., furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.); (ii) anaromatic fused heterocyclic group (e.g., benzofuranyl, isobenzofuranyl,benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,benzoxazolyl, 1,2-benzisothiazolyl, 1H-benztriazolyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl,phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.);and (iii) a non-aromatic, heterocyclic group (e.g., oxiranyl,azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,piperazinyl, etc.).

Examples of sulfinyl group in an optionally substituted sulfinyl groupas the substituent of the 5- to 7-membered ring include that where —SO—is combined with “the hydrocarbon group” or “the heterocyclic group” in“an optionally substituted hydrocarbon group” or “an optionallysubstituted heterocyclic group” of the substituent of the 5- to7-membered ring.

Preferred examples include a C₁₋₈ alkylsulfinyl group where sulfinylgroup is combined with a C₁₋₈ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.; a C₆₋₁₀arylsulfinyl group where sulfinyl group is combined with a C₆₋₁₀ arylgroup such as phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl,4-indanyl, 5-indanyl, 5,6,7,8-tetrahydro-1-naphthyl,5,6,7,8-tetrahydro-2-naphthyl, 5,6-dihydro-1-naphthyl,5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4-naphthyl,etc.; a group where sulfinyl group is combined with an aromaticmonocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazinyl, etc.); and a group where sulfinylgroup is combined with an aromatic fused heterocyclic group (e.g.,benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl,1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisothiazolyl,1H-benztriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolizinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl, etc.).

More preferred examples include a C₁₋₈ alkylsulfinyl group wheresulfinyl group is combined with a C₁₋₈ alkyl group such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl,octyl, etc.

Examples of sulfonyl group in an optionally substituted sulfonyl groupas the substituent of the 5- to 7-membered ring include a group where—SO₂— is combined with “the hydrocarbon group” or “the heterocyclicgroup” in “an optionally substituted hydrocarbon group” or “anoptionally substituted heterocyclic group” of the substituent of the 5-to 7-membered ring.

Preferred examples include a C₁₋₈ alkylsulfonyl group where sulfonylgroup is combined with a C₁₋₈ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.; a C₆₋₁₀arylsulfonyl group where sulfonyl group is combined with a C₆₋₁₀ arylgroup such as phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl,4-indanyl, 5-indanyl, 5,6,7,8-tetrahydro-1-naphthyl,5,6,7,8-tetrahydro-2-naphthyl, 5,6-dihydro-1-naphthyl,5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4-naphthyl,etc.; a group where sulfonyl group is combined with an aromaticmonocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazinyl, or the like); and a group where thesulfonyl group is combined with an aromatic, fused heterocyclic group(e.g., benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl,isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,1,2-benzisothiazolyl, 1H-benztriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl, etc.).

More preferred examples include a C₁₋₈ alkylsulfonyl group wheresulfonyl group is combined with a C₁₋₈ alkyl group such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl,octyl, etc.

Examples of an optionally substituted hydroxyl group as the substituentof the 5- to 7-membered ring include hydroxyl group and that having anappropriate substituent, for example, “an optionally substitutedhydrocarbon group” or “an optionally substituted heterocyclic group” ofthe above substituent of the 5- to 7-membered ring.

Preferred examples include a C₁₋₈ alkyloxy group whose substituent is aC₁₋₈ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.; a C₆₋₁₀ aryloxy groupwhose substituent is a C₆₋₁₀ aryl group such as phenyl, α-naphthyl,β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl,5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl,5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl,5,6-dihydro-4-naphthyl, etc.; a hydroxyl group substituted with anaromatic monocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazinyl, etc.); a hydroxyl group substitutedwith an aromatic fused heterocyclic group (e.g., benzofuranyl,isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 1H-benztriazolyl,quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl,phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl,α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl,phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolizinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl, etc.).

More preferred examples include a C₆₋₁₀ aryloxy group (in particular,phenyloxy) or a hydroxyl group substituted with an aromatic monocyclicheterocyclic group (in particular, pyridyl) or an aromatic fusedheterocyclic group (in particular, quinolyl).

“The hydrocarbon group” or “the heterocyclic group” as the substituentof the substituted hydroxyl group exemplified above may have the samesubstituent as that of “the hydrocarbon group” or “the heterocyclicgroup” in “an optionally substituted hydrocarbon group or an optionallysubstituted heterocyclic group” of the substituent of the 5- to7-membered ring.

Examples of an optionally substituted thiol group as the substituent ofthe 5- to 7-membered ring include thiol group and that substituted withan appropriate group such as “an optionally substituted hydrocarbongroup” or “an optionally substituted heterocyclic group” of thesubstituent of the 5- to 7-membered ring.

Preferred examples include a C₁₋₈ alkylthio group, whose substituent isa C₁₋₈ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.; a C₆₋₁₀ arylthiogroup, whose substituent is a C₆₋₁₀ aryl group such as phenyl,α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl,5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl,5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl,5,6-dihydro-4-naphthyl, etc.; a thiol group substituted with an aromaticmonocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, triazinyl, etc.); and a thiol group substitutedwith an aromatic fused heterocyclic groups (e.g., benzofuranyl,isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl,benzimidazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl,quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl,phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl,α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl,phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolizinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl, etc.).

“The hydrocarbon group” or “the heterocyclic group” as the substituentof the substituted thiol group exemplified above may have the samesubstituent as that of “the hydrocarbon group” or “the heterocyclicgroup” in “an optionally substituted hydrocarbon group” or “anoptionally substituted heterocyclic group” of the substituent of the 5-to 7-membered ring.

More preferred examples include a C₁₋₈ alkylthio group substituted witha C₁₋₈ alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl,isohexyl, heptyl, octyl, or the like.

Examples of an optionally substituted amino group as the substituent ofthe 5- to 7-membered ring include amino group, an N-mono-substitutedamino group, and an N,N-di-substituted amino group. Examples of saidsubstituted amino groups include that having one or two substituents ofan optionally substituted hydrocarbon group (e.g., the same group as anoptionally substituted hydrocarbon group of the substituent of the 5- to7-membered ring, more specifically, a C₁₋₈ alkyl group, a C₃₋₇cycloalkyl group, a C₂₋₈ alkenyl group, a C₂₋₈ alkynyl group, a C₃₋₇cycloalkenyl group, a C₆₋₁₀ aryl group that may have a C₁₋₄ alkyl group,etc.), an optionally substituted heterocyclic group (e.g., the samegroup as an optionally substituted heterocyclic group of the substituentof the 5- to 7-membered ring), or the formula: —COR′ (wherein R′represents hydrogen atom or an optionally substituted hydrocarbon groupor an optionally substituted heterocyclic group. As for “the hydrocarbongroup” or “the heterocyclic group” in “an optionally substitutedhydrocarbon group” or “an optionally substituted heterocyclic group” ofR′ may have the same substituent as that of “the hydrocarbon group” or“the heterocyclic group” in “an optionally substituted hydrocarbongroup” or “an optionally substituted heterocyclic group” of thesubstituent of the 5- to 7-membered ring), preferably a C₁₋₁₀ acyl group(e.g., a C₂₋₇ alkanoyl, benzoyl, nicotinoyl, etc.). Specific examplesthereof include methylamino, dimethylamino, ethylamino, diethylamino,dipropylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino,N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino,nicotinoylamino, and the like.

In addition, the two groups in said substituted amino groups may becombined to form a nitrogen-containing 5- to 7-membered ring (e.g.,piperidino, piperdino, morpholino, thiomorpholino, etc.).

Examples of the optionally substituted acyl group as the substituent ofthe 5- to 7-membered ring include (i) formyl or (ii) a group where thecarbonyl group is combined with a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenylgroup, a C₂₋₁₀ alkynyl group, a C₃₋₇ cycloalkyl group, a C₅₋₇cycloalkenyl group, or an aromatic group (e.g., phenyl group, pyridylgroup, etc.) (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, etc.)and the like.

Examples of the optionally esterified carboxyl group as the substituentof the 5- to 7-membered ring include, in addition to carboxyl group, analkyloxycarbonyl group, an alkenyloxycarbonyl, an alkenyloxycarbonyl, anaralkyloxycarbonyl group, an acyloxycarbonyl group, an aryloxycarbonylgroup, and the like.

Examples of the alkyl group in said alkyloxycarbonyl group include aC₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, etc.).

Examples of the alkenyl group in said alkenyloxycarbonyl group include aC₂₋₆ alkenyl group (e.g., vinyl, allyl, isopropenyl, 1-propenyl,1-butenyl, 2-butenyl, 3-methylallyl, etc.).

Examples of the alkynyl group in said alkenyloxycarbonyl group include aC₂₋₆ alkynyl group (e.g., ethynyl, 2-propynyl, etc.).

The aralkyl group in said aralkyloxycarbonyl group means an aryl-alkylgroup (e.g., C₆₋₁₀ aryl-C₁₋₆ alkyl, etc.). The aryl group in saidaryl-alkyl group means a monocyclic or condensed polycyclic aromatichydrocarbon group, and preferred examples include phenyl, naphthyl,anthryl, phenanthryl, acenaphthenyl, and the like. They may have asubstituent such as a C₁₋₁₀ alkyl group, a C₂₋₁₀ alkenyl group, a C₂₋₁₀alkynyl group, a C₃₋₈ cycloalkyl group, a C₃₋₈ cycloalkenyl group, aC₄₋₈ cycloalkadienyl group, an aryl group (e.g., C₆₋₁₄ aryl, etc.), anaromatic heterocyclic group (e.g., the same aromatic heterocyclic groupas that of the substituent of the hydrocarbon group, the acyl group, thesulfonyl group, the sulfinyl group and the heterocyclic group of theabove substituent of the 5- to 7-membered ring, etc.), a non-aromaticheterocyclic group (e.g., the same non-aromatic heterocyclic group asthat of the substituent of the hydrocarbon group, the acyl group, thesulfonyl group, the sulfinyl group and the heterocyclic group of theabove substituent of the 5- to 7-membered ring, etc.), an aralkyl group(e.g., a C₆₋₁₄ aryl-C₁₋₆ alkyl group, etc.), amino group, anN-mono-substituted amino group (e.g., the same N-mono-substituted aminogroup as that of the substituent of the hydrocarbon group, the acylgroup, the sulfonyl group, the sulfinyl group and the heterocyclic groupof the above substituent of the 5- to 7-membered ring, preferably aN-mono-C₁₋₄ alkylamino group, etc.), a N,N-disubstituted amino group(e.g., the same N,N-disubstituted amino group as that of the substituentin the hydrocarbon group, the acyl group, the sulfonyl group, thesulfinyl group and the heterocyclic group of the above substituent ofthe 5- to 7-membered ring, preferably a N,N-di-C₁₋₄ alkylamino group,etc.), amidino group, an acyl group (e.g., the same acyl group as thatof the substituent of the hydrocarbon group, the acyl group, thesulfonyl group, the sulfinyl group and the heterocyclic group of theabove substituent of the 5- to 7-membered ring, etc.), carbamoyl group,a N-mono-substituted carbamoyl group (e.g., a N-mono-C₁₋₄alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl, etc.;phenylcarbamoyl; etc.), a N,N-disubstituted carbamoyl group (aN,N-di-C₁₋₄ alkyl-carbamoyl group such as N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, etc.; piperidinocarbamoyl; morpholinocarbamoyl;etc.), sulfamoyl group, a N-mono-substituted sulfamoyl group (e.g., aN-mono-C₁₋₄ alkylsulfamoyl group such as methylsulfamoyl,ethylsulfamoyl, etc.; phenylsulfamoyl; p-toluenesulfamoyl; etc.), aN,N-disubstituted sulfamoyl group (e.g., a N,N-disubstituted C₁₋₄alkylsulfamoyl group such as N,N-dimethylsulfamoyl, etc.; a N—C₁₋₄alkyl-N-phenylsulfamoyl group such as N-methyl-N-phenylsulfamoyl, etc.;piperidinosulfamoyl; morpholinosulfamoyl; etc.), carboxyl group, a C₁₋₁₀alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, etc.), hydroxyl group, a C₁₋₁₀ alkoxy group, aC₂₋₁₀ alkenyloxy group, a C₃₋₇ cycloalkyloxy group, an aralkyloxy group(e.g., C₆₋₁₄ aryl-C₁₋₆ alkyloxy, etc.), an aryloxy group (e.g., C₆₋₁₄aryloxy, etc.), mercapto group, a C₁₋₁₀ alkylthio group, an aralkylthiogroup (e.g., C₆₋₁₄ aryl-C₁₋₆ alkylthio, etc.), an arylthio group (e.g.,C₆₋₁₄ arylthio, etc.), sulfo group, cyano group, azido group, nitrogroup, nitroso group, a halogen atom, or the like. As for an alkyl groupin said aryl-alkyl group, a C₁₋₆ alkyl group (e.g., methyl, ethyl,propyl, butyl, etc.) is preferred. Preferred examples of said aralkylgroup, i.e., an aryl-alkyl group include benzyl, phenethyl,3-phenylpropyl, (1-naphthyl)methyl, (2-naphthyl)methyl, and the like.Among them, benzyl, phenethyl, and the like are preferred.

As the acyl group in said acyloxycarbonyl group, for example, there areformyl, a C₂₋₄ alkanoyl group, a C₃₋₄ alkenoyl group, a C₃₋₄ alkynoxylgroup, and the like.

As the aryl group in said aryloxycarbonyl group, for example, there arephenyl, naphthyl, and the like.

Examples of the amidated carboxyl group as the substituent of thehydrocarbon group, the acyl group, the sulfonyl group, the sulfinylgroup and the heterocyclic group of the substituent of the 5- to7-membered ring include the carboxyl group amidated with an optionallysubstituted amino group as the substituent of the hydrocarbon group, theacyl group, the sulfonyl group, and the heterocyclic group of the abovesubstituent of the 5- to 7-membered ring, each of which may besubstituted.

Example of an optionally substituted phosphoryl group of the substituentof the 5- to 7-membered ring include phosphoryl group, a (C₁₋₆alkoxy)phosphoryl group such as ethoxyphosphoryl, a di-(C₁₋₆alkoxy)phosphoryl group such as diethoxyphosphoryl, etc.; a lower (C₁₋₆)alkyl group substituted with an optionally esterified phosphono groupsuch as a phosphono-C₁₋₆ alkyl group, a C₁₋₆ alkoxyphosphoryl-C₁₋₆ alkylgroup, a di-(C₁₋₆ alkoxy)phosphoryl-C₁₋₆ alkyl group such asdiethoxyphosphorylmethyl, etc.; and the like.

“The hydrocarbon group”, “the heterocyclic group”, “the sulfinyl group”,or “the sulfonyl group” in “an optionally substituted hydrocarbongroup”, “an optionally substituted heterocyclic group”, “an optionallysubstituted sulfinyl group”, or “an optionally substituted sulfonylgroup” of the substituent of the 5- to 7-membered ring may be furthersubstituted with 1 to 3 substituents. Examples of said substituentsinclude a lower (C₁₋₆) alkyl group (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, etc.); a lower (C₂₋₆) alkenyl group (e.g., vinyl,allyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.);a lower (C₂₋₆) alkynyl group (e.g., ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl,etc.); a C₃₋₇ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, etc.); a C₆₋₁₀ aryl group (e.g.,phenyl, α-naphthyl, β-naphthyl, etc.); an aromatic heterocyclic group[e.g., (i) an aromatic 5- or 6-membered heterocyclic group having 1-4heteroatoms selected from nitrogen atom, oxygen atom, and sulfur atom;(ii) a fused bicyclic heterocyclic group formed by condensation of anaromatic 5- or 6-membered heterocyclic group having 1 to 3 heteroatomsselected from nitrogen atom, oxygen atom, and sulfur atom with benzenering or an aromatic 5- or 6-membered heterocyclic group having 1 to 3heteroatoms selected from nitrogen atom, oxygen atom, and sulfur atom;(iii) a fused tricyclic heterocyclic group formed by condensation of [1]an aromatic, 5- or 6-membered heterocyclic group having 1-3 heteroatomsselected from nitrogen atom, oxygen atom and sulfur atom, [2] benzenering, and [3] an aromatic 5- or 6-membered heterocyclic group having 1-3heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom orbenzene ring, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo[b]thienyl,indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,1,2-benzisothiazolyl, 1H-benztriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl, etc.]; a heterocyclic-oxy group formedby combining each of the above heterocyclic groups (i), (ii) and (iii)with oxy group; a non-aromatic heterocyclic group (e.g., a non-aromatic,4- or 7-membered heterocyclic group having 1 to 3 heteroatoms selectedfrom nitrogen atom, oxygen atom and sulfur atom, such as oxiranyl,azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,piperazinyl, etc.); a C₇₋₁₄ aralkyl group (e.g., a C₆₋₁₀ aryl-C₁₋₄ alkylgroup such as benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl,2-phenylpropyl, 3-phenylpropyl, α-naphthylmethyl, α-naphthylethyl,β-naphthylmethyl, β-naphthylethyl, etc.); amino group; aN-mono-substituted amino group [e.g., a N—(C₁₋₆ alkyl)amino group suchas methylamino, ethylamino, allylamino, cyclohexylamino, phenylamino, aN—(C₂₋₆ alkenyl)amino group, a N—(C₃₋₇ cycloalkyl)amino group, aN—(C₆₋₁₀ aryl)amino group, etc.]; a N,N-disubstituted amino group [e.g.,an amino group substituted with two substituents selected from a C₁₋₆alkyl group, a C₂₋₆ alkenyl group, a C₃₋₇ cycloalkenyl group, and aC₆₋₁₀ aryl group, such as dimethylamino, diethylamino, dibutylamino,diallylamino, N-methyl-N-phenylamino, etc.]; amidino group; an acylgroup (e.g., formyl, a C₂₋₈ alkanoyl group such as acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,octanoyl, cyclopropanecarbonyl, cyclobutanecarbonyl,cyclopentanecarbonyl, cyclohexanecarbonyl, crotonyl,2-cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.; a C₃₋₈ alkenoyl group;a C₃₋₇ cycloalkyl-carbonyl group; a C₃₋₇ cycloalkenyl-carbonyl group; aC₆₋₁₀ aryl-carbonyl group; a heterocyclic-carbonyl group formed bybinding of an aromatic or non-aromatic 5- or 6-membered heterocyclicgroup having 1-3 heteroatoms selected from nitrogen atom, oxygen atomand sulfur atom with carbonyl group, etc.); carbamoyl group; amono-substituted carbamoyl group [e.g., a N—(C₁₋₆ alkyl)carbamoyl groupsuch as methylcarbamoyl, ethylcarbamoyl, cyclohexylcarbamoyl,phenylcarbamoyl, etc.]; a N—(C₂₋₆ alkenyl)carbamoyl group; a N—(C₃₋₇cycloalkyl)carbamoyl group; a N—(C₆₋₁₀ aryl)carbamoyl group; etc.]; aN,N-disubstituted carbamoyl group [e.g., a carbamoyl group substitutedwith two substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₇ cycloalkyl group, and a C₆₋₁₀ aryl group, such asdimethylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, diallylcarbamoyl,N-methyl-N-phenylcarbamoyl, etc.]; sulfamoyl group, a N-mono-substitutedsulfamoyl group [e.g., a N—(C₁₋₆ alkyl)sulfamoyl group such asmethylsulfamoyl, ethylsulfamoyl, cyclohexylsulfamoyl, phenylsulfamoyl,etc.; a N—(C₂₋₆ alkenyl)sulfamoyl group; a N—(C₃₋₇ cycloalkyl)sulfamoylgroup; a N—(C₆₋₁₀ aryl)sulfamoyl group; etc.], a N,N-disubstitutedsulfamoyl group [e.g., sulfamoyl group substituted with two substituentsselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₇cycloalkyl group, and a C₆₋₁₀ aryl group, such as dimethylsulfamoyl,diethylsulfamoyl, dibutylsulfamoyl, diallylsulfamoyl,N-methyl-N-phenylsulfamoyl, etc.]; carboxyl group; a lower (C₁₋₆)alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl, etc.); hydroxyl group; a lower (C₁₋₆) alkoxy group(e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.); a lower (C₂₋₁₀)alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy,3-hexenyloxy, etc.); a C₃₋₇ cycloalkyloxy group (e.g., cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.); aC₆₋₁₀ aryloxy group (e.g., phenoxy, naphthyloxy, etc.); a C₇₋₁₄aralkyloxy group (e.g., a C₆₋₁₀ aryl-C₁₋₄ alkyloxy group such asphenyl-C₁₋₄ alkyloxy, naphthyl-C₁₋₄ alkyloxy, etc.); mercapto group; alower (C₁₋₆)alkylthio group (e.g., methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio,pentylthio, isopentylthio, neopentylthio, hexylthio, etc.), a C₇₋₁₄aralkylthio group (e.g., a C₆₋₁₀ aryl-C₁₋₄ alkylthio group such asphenyl-C₁₋₄ alkylthio, naphthyl-C₁₋₄ alkylthio, etc.); a C₆₋₁₀ arylthiogroup (e.g., phenylthio, naphthylthio, etc.), a lower (C₁₋₆)alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl,propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfanyl,sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfanyl,isopentylsulfanyl, neopentylsulfanyl, hexylsulfinyl, etc.); a C₇₋₁₄aralkylsulfinyl group (e.g., a C₆₋₁₀ aryl-C₁₋₄ alkylsulfinyl group suchas phenyl-C₁₋₄ alkylsulfinyl, naphthyl-C₁₋₄ alkylsulfinyl, etc.); aC₆₋₁₀ arylsulfinyl group (e.g., phenylsulfinyl, naphthylsulfinyl, etc.);a lower (C₁₋₆) alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl,sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl,isopentylsulfanyl, neopentylsulfanyl, hexylsulfonyl, etc.), a C₇₋₁₄aralkylsulfonyl group (e.g., a C₆₋₁₀ aryl-C₁₋₄ alkylsulfonyl group suchas phenyl-C₁₋₄ alkylsulfonyl, naphthyl-C₁₋₄ alkylsulfonyl, etc.), aC₆₋₁₀ arylsulfonyl group (e.g., phenylsulfonyl, naphthylsulfonyl, etc.);sulfo group; cyano group; azido group; a halogen atom (e.g., fluorine,chlorine, bromine, iodine, etc.); nitro group; nitroso group; anoptionally esterified phosphono group [e.g., phosphono group, a (C₁₋₆alkoxy)phosphoryl group such as ethoxyphosphoryl, a di-(C₁₋₆alkoxy)phosphoryl group such as diethoxyphosphoryl, etc.]; a lower(C₁₋₆) alkyl group substituted with an optionally esterified phosphonogroup (e.g., a phosphono-C₁₋₆ alkyl group, a C₁₋₆ alkoxyphosphoryl-C₁₋₆alkyl group, a di-(C₁₋₆ alkoxy)phosphoryl-C₁₋₆ alkyl group such asdiethoxyphosphorylmethyl, etc.); a C₁₋₆ haloalkyl group (e.g., a C₁₋₆alkyl group substituted with 1 to 4 halogen such as trifluoromethyl,etc.); a C₁₋₆ haloalkoxy group (e.g., a C₁₋₆ alkoxy group substitutedwith 1 to 4 halogen such as trifluoromethoxy, etc.); and the like.

Among the above substituents, when hydroxyl group is located adjacent toa lower (C₁₋₆) alkoxy group, they may form C₁₋₆ alkylenedioxy groupssuch as methylenedioxy, ethylenedioxy, or the like.

The above C₆₋₁₀ aryl group, the C₆₋₁₀ aryl group as a substituent of thearomatic heterocyclic group and the N-mono-substituted amino group, theC₆₋₁₀ aryl group as a substituent of the N,N-di-substituted amino group,the C₆₋₁₀ aryl group as a substituent of the N-mono-substitutedcarbamoyl group, the C₆₋₁₀ aryl group as a substituent of theN,N-di-substituted carbamoyl group, the C₆₋₁₀ aryl as a substituent ofthe N-mono-substituted sulfamoyl group, the C₆₋₁₀ aryl group as asubstituent of the N,N-disubstituted sulfamoyl group, the C₆₋₁₀ arylgroup as a substituent of the C₆₋₁₀ aryloxy group, the C₆₋₁₀ aryl groupof the C₇₋₁₄ aralkyloxy group, the C₆₋₁₀ aryl group of the C₇₋₁₄aralkylthio groups, the C₆₋₁₀ aryl group of the C₆₋₁₀ arylthio groups,the C₆₋₁₀ aryl group of the C₇₋₁₄ aralkylsulfinyl groups, the C₆₋₁₀ arylgroup of the C₆₋₁₀ arylsulfinyl group, the C₆₋₁₀ aryl group of the C₇₋₁₄aralkylsulfonyl groups, and the C₆₋₁₀ aryl group in the C₆₋₁₀arylsulfonyl group may be substituted further with 1 to 3 substituents.Examples of said substituent include a lower (C₁₋₆) alkyl group, aminogroup, a N—(C₁₋₆ alkyl)amino group, a N,N-di-(C₁₋₆ alkyl)amino group,amidino group, carbamoyl group, a N—(C₁₋₆ alkyl)carbamoyl group, aN,N-di-(C₁₋₆ alkyl)carbamoyl group, sulfamoyl group, a N—(C₁₋₆alkyl)sulfamoyl group, a N,N-di-(C₁₋₆ alkyl)sulfamoyl group, carboxylgroup, a lower (C₂₋₇) alkoxycarbonyl group, hydroxyl group, a lower(C₁₋₆) alkoxy group, mercapto group, a lower (C₁₋₆) alkylthio group,sulfo group, cyano group, azido group, a halogen atom, nitro group,nitroso group, an optionally substituted phosphono group [e.g.,phosphono group, a C₁₋₆ alkoxyphosphoryl group, a di-(C₁₋₆alkoxy)phosphoryl group, etc.], a lower (C₁₋₆) alkyl group substitutedwith an optionally esterified phosphono group [e.g., a phosphono-C₁₋₆alkyl group, a C₁₋₆ alkoxyphosphoryl-C₁₋₆ alkyl group, a di-(C₁₋₆alkoxy)phosphoryl-C₁₋₆ alkyl group such as diethoxyphosphorylmethyl,etc.], and the like.

Among the above substituent, when hydroxyl group is located adjacent toa lower (C₁₋₆) alkoxyl group, they may form a C₁₋₆ alkylenedioxy groupsuch as methylenedioxy, ethylenedioxy, or the like.

The number of the substituents of the 5- to 7-membered ring is 1 to 3,preferably 1 to 2 and the substituents may be the same or different andpresent at any possible positions of the ring.

Q of the formula (II) is C, CR⁵, or N.

R⁵ is H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, cyano group, a halogen atom, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- is —CO—, —CS—, —SO— or —SO₂—, and Z² is anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group, an optionally substituted hydroxyl group, or anoptionally substituted amino group).

Examples of an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group and anoptionally substituted heterocyclic group of R⁵ or Z² include the samegroups as those exemplified with respect to the above substituents ofthe 5- to 7-membered ring of ring A.

Examples of halogen and an optionally substituted thiol group of R⁵include the same groups as those exemplified with respect to the abovesubstituent of the 5- to 7-membered ring of ring A.

X¹ in the formulas (I) and (II) is CR¹, CR¹R², N or NR¹³.

R¹ is H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, cyano group, a halogen atom, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- and Z² are as defined above).

Examples of an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, halogen and an optionallysubstituted heterocyclic group of R¹ include the same groups as thoseexemplified with respect to the substituents of the 5- to 7-memberedring of ring A.

R² is H, or an optionally substituted hydrocarbon group, and examples ofan optionally substituted hydrocarbon group of R² include the same groupas that exemplified with respect to the substituent of the 5- to7-membered ring of ring A.

R¹³ is H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- and Z² are as defined above).

Examples of an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group and anoptionally substituted heterocyclic group of R¹³ include the same groupsas those exemplified with respect to the substituents of the 5- to7-membered ring of ring A.

R¹ of the formula (III) is H, an optionally substituted hydrocarbongroup, an optionally substituted hydroxyl group, an optionallysubstituted thiol group, an optionally substituted amino group, cyanogroup, a halogen atom, an optionally substituted heterocyclic group, ora group of the formula: -Z¹-Z² (wherein -Z¹- is —CO—, —CS—, —SO— or—SO₂—, and Z² is an optionally substituted hydrocarbon group, anoptionally substituted heterocyclic group, an optionally substitutedhydroxyl group, or an optionally substituted amino group).

In R¹ of the formula (III), preferred example of the group of theformula: -Z¹-Z² is a group of the formula: —CONR²⁰(CR²¹R²²R²³), whereinR²⁰ is H or an optionally substituted hydrocarbon group, and R²¹, R²²,and R²³ are the same or different and are an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, or R²⁰and R²¹ may be combined to form a ring.

Examples of an optionally substituted hydrocarbon group of R¹, R²⁰, R²¹,R²² and R²³, an optionally substituted heterocyclic group of R¹, R²¹,R²² and R²³, and an optionally substituted hydroxyl group, an optionallysubstituted amino group, an optionally substituted thiol group andhalogen of R¹ include the same groups as those exemplified with respectto the substituents of the 5- to 7-membered ring of ring A of theformulas (I) and (II).

Preferably, at least one of R²¹, R²² and R²³ is an optionallysubstituted heterocyclic group which may be fused with an optionallysubstituted benzene ring, or an optionally substituted phenyl groupwhich may be fused with an optionally substituted aromatic heterocyclicring.

Examples of the “fused heterocyclic group” of the “optionallysubstituted heterocyclic group which may be fused with an optionallysubstituted benzene ring” and the “fused phenyl group” of the“optionally substituted phenyl group which may be fused with anoptionally substituted aromatic heterocyclic ring” of R²¹, R²² and R²³include the same groups as those exemplified with respect to thearomatic fused heterocyclic group as the substituents of the 5- to7-membered ring of ring A.

Examples of these substituents include the same groups as thoseexemplified with respect to the substituents of the 5- to 7-memberedring of ring A of the formulas (I) and (II).

The ring formed in combination with R²⁰ and R²¹ is preferably anoptionally substituted 5- to 7-membered ring, more preferably anoptionally substituted 5- or 6-membered ring, and may be fused with anoptionally substituted benzene ring. Such rings include the same ringsas those exemplified with respect to the “5- to 7-membered ring” of “anoptionally substituted 5- to 7-membered ring” in the ring A of theformulas (I) and (II).

These rings may have 1 to 3 substituents selected from the groupconsisting of (1) halogen, (2) hydrogen, (3) a phenoxy which may besubstituted with 1 to 3 substituents selected from halogen, hydroxyl,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl (e.g., formyl, C₂₋₆ alkanoyl, etc.),cyano, amino, mono-C₁₋₆ alkyl-amino, di-C₁₋₆ alkyl-amino, C₁₋₆alkyl-sulfanyl, C₁₋₆ alkyl-sulfinyl, C₁₋₆ alkyl-sulfonyl, C₁₋₆alkoxy-carbonyl, carbamoyl, N—C₁₋₆ alkyl-carbamoyl and N,N-di-C₁₋₆alkyl-carbamoyl,

(4) C₁₋₆ alkoxy which may be substituted with 1 to 3 substituentsselected from halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl,cyano, amino, mono-C₁₋₆ alkyl-amino, di-C₁₋₆ alkyl-amino, C₁₋₆alkyl-sulfanyl, C₁₋₆ alkyl-sulfinyl, C₁₋₆ alkyl-sulfonyl, C₁₋₆alkoxy-carbonyl, carbamoyl, N—C₁₋₆ alkyl-carbamoyl, N,N-di-C₁₋₆alkyl-carbamoyl and phenyl which may be substituted with 1 to 3substituents selected from halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ acyl, cyano, halogeno C₁₋₆ alkyl (e.g., trifluoromethyl, etc.),amino, mono-C₁₋₆ alkyl-amino, di-C₁₋₆ alkyl-amino, C₁₋₆ alkyl-sulfanyl,C₁₋₆ alkyl-sulfinyl, C₁₋₆ alkyl-sulfonyl, C₁₋₆ alkoxy-carbonyl,carbamoyl, N—C₁₋₆ alkyl-carbamoyl and N,N-di-C₁₋₆ alkyl-carbamoyl,and (5) a C₁₋₈ hydrocarbon group (e.g., C₁₋₈ alkyl, C₃₋₇ cycloalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₇ cycloalkenyl, etc.) which may besubstituted with 1 to 3 substituents selected from halogen, hydroxyl,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl, cyano, amino, mono-C₁₋₆ alkyl-amino,di-C₁₋₆ alkyl-amino, C₁₋₆ alkyl-sulfanyl, C₁₋₆ alkyl-sulfinyl, C₁₋₆alkyl-sulfonyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, N—C₁₋₆ alkyl-carbamoyl,N,N-di-C₁₋₆ alkyl-carbamoyl and phenyl which may be substituted with 1to 3 substitutents selected from halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ acyl, cyano, halogeno C₁₋₆ alkyl (e.g., trifluoromethyl,etc.), amino, mono-C₁₋₆ alkyl-amino, di-C₁₋₆ alkyl-amino, C₁₋₆alkyl-sulfanyl, C₁₋₆ alkyl-sulfinyl, C₁₋₆ alkyl-sulfonyl, C₁₋₆alkoxy-carbonyl, carbamoyl, N—C₁₋₆ alkyl-carbamoyl and N,N-di-C₁₋₆alkyl-carbamoyl.

Specific examples of these substituents include the same groups as thoseexemplified with respect to the substituents of the 5- to 7-memberedring of ring A of the formulas (I) and (II).

R^(1a) of the formula (IIIa) is (1) an optionally substitutedheterocyclic group or (2) a group of the formula: -Z^(1a)-Z^(2a)(wherein -Z^(1a)- is —CO—, —CS—, —SO— or —SO₂—, and Z^(2a) is (i) anoptionally substituted heterocyclic group, (ii)—NR^(20a)(CR^(21a)R^(22a)R^(23a)) (wherein (a) R^(20a) is H or anoptionally substituted hydrocarbon group; and R^(21a) is an optionallysubstituted heterocyclic group which may be fused with an optionallysubstituted benzene ring, or an optionally substituted C₆₋₁₀ aryl groupwhich may be fused with an optionally substituted aromatic heterocyclicring and R^(22a) and R^(23a) are the same or different and are anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group or R^(22a) and R^(23a) may be combined to form aring, or (b) R^(20a) is H or an optionally substituted hydrocarbongroup; and R^(21a), R^(22a) and R^(23a) are the same or different andare an optionally substituted C₁₋₈ aliphatic hydrocarbon group, providedthat the sum total of the number of carbon atoms is 7 or more),

(iii) —NR^(20a)R^(25a) (wherein R^(20a) is as defined above and R^(25a)is an optionally substituted C₆₋₁₀ aryl-C₂₋₄ alkyl, C₆₋₁₀ aryloxy-C₂₋₄alkyl, C₆₋₁₀ arylamino-C₂₋₄ alkyl, C₇₋₁₄ aralkylamino-C₂₋₄ alkyl,heterocyclic ring-C₂₋₄ alkyl or heterocyclic group), (iv) a substituted5- to 7-membered cyclic amino group, or (v) —OR^(24a) (wherein R^(24a)is (a) an optionally substituted C₇₋₁₄ aralkyl group, (b) an optionallysubstituted C₃₋₇ alicyclic hydrocarbon group, (c) an optionallysubstituted C₇₋₂₄ aliphatic hydrocarbon group, or (d) an optionallysubstituted heterocyclic group)).

Examples of an optionally substituted hydrocarbon group of R^(20a),R^(22a) and R^(23a) and an optionally substituted heterocyclic group ofR^(1a), R^(2a), R^(21a), R^(22a) and R^(23a) include the same groups asthose exemplified with respect to the substituents of the 5- to7-membered ring of ring A of the formulas (I) and (II).

Examples of the “fused heterocyclic group” of the “optionallysubstituted heterocyclic group which may be fused with an optionallysubstituted benzene ring” and the “fused phenyl group” of “an optionallysubstituted phenyl group which may be fused with an optionallysubstituted aromatic heterocyclic ring” of R^(21a), R^(22a) and R^(23a)include the same groups as those exemplified with respect to thearomatic fused heterocyclic group as the substituents of the 5- to7-membered ring of ring A.

Examples of the ring formed in combination with R^(20a) and R^(21a) andthe substituents thereof include the same rings and substituents asthose exemplified with respect to the ring formed in combination withR²⁰ and R²¹ and the substituents thereof.

Examples of the “optionally substituted C₁₋₈ aliphatic hydrocarbongroup” of R^(20a) include the same groups as those exemplified withrespect to the aliphatic hydrocarbon group as the substituents of the 5-to 7-membered ring of ring A.

Examples of the “optionally substituted C₇₋₁₄ aralkyl group”, the“optionally substituted C₃₋₇ alicyclic hydrocarbon group” and the“optionally substituted heterocyclic group” of R^(24a) include the samegroups as those exemplified with respect to the substituents of the 5-to 7-membered ring of ring A respectively.

Examples of the “C₇₋₂₄ aliphatic hydrocarbon group” of the “optionallysubstituted C₇₋₂₄ aliphatic hydrocarbon group” in R^(24a) include, forexample, C₇₋₂₄ alkyl, C₇₋₂₄ alkenyl, C₇₋₂₄ alkynyl, C₇₋₂₄ alkadienyl,C₇₋₂₄ alkadienyl such as heptyl, octyl, 1-heptenyl, 1-octenyl,1-heptynyl, 1-octynyl, etc.

Examples of the substituents of the “optionally substituted C₇₋₂₄aliphatic hydrocarbon group” in R^(24a) include the same substituents asthose exemplified with respect to the substituents of the hydrocarbongroup as the substituents of 5- to 7-membered ring of ring A.

In the formula (IIIa), R^(1a) is preferably (1) an optionallysubstituted 5- to 7-membered aromatic or non-aromatic heterocyclic grouphaving 1-4 hetero atoms selected from nitrogen atom, oxygen atom andsulfur atom, or (2) a group of the formula: —CO-Z^(2c) (wherein Z^(2c)is (i) an optionally substituted 5- to 7-membered aromatic ornon-aromatic heterocyclic group having 1-4 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom, (ii) —NR^(20c)(CR^(21c)R^(22c)R^(23c)) (wherein (a) R^(20c) is H or an optionallysubstituted hydrocarbon group selected from C₁₋₈ saturated aliphatichydrocarbon group, C₂₋₈ unsaturated aliphatic hydrocarbon group, C₃₋₇saturated alicyclic hydrocarbon group, C₃₋₇ unsaturated alicyclichydrocarbon group, C₉₋₁₀ partly saturated and fused bicyclic hydrocarbongroup, C₃₋₇ saturated or unsaturated alicyclic-C₁₋₈ saturated orunsaturated aliphatic hydrocarbon group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon-C₁₋₄ alkyl group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon-C₂₋₄ alkenyl group, C₆₋₁₀ aryl group andC₇₋₁₄ aralkyl group; and R^(21c) is 1) an optionally substituted 5- to7-membered aromatic or non-aromatic heterocyclic group having 1-4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, whichmay be fused with an optionally substituted benzene ring, or 2) anoptionally substituted C₆₋₁₀ aryl group (e.g., phenyl group, etc.) whichmay be fused with an optionally substituted 5- to 7-membered aromaticheterocyclic ring having 1-4 hetero atoms selected from nitrogen atom,oxygen atom and sulfur atom; and R^(22c) and R^(23c) are the same ordifferent and are an optionally substituted hydrocarbon group selectedfrom C₁₋₈ saturated aliphatic hydrocarbon group, C₂₋₈ unsaturatedaliphatic hydrocarbon group, C₃₋₇ saturated alicyclic hydrocarbon group,C₃₋₇ unsaturated alicyclic hydrocarbon group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon group, C₃₋₇ saturated or unsaturatedalicyclic-C₁₋₈ saturated or unsaturated aliphatic hydrocarbon group,C₉₋₁₀ partly saturated and fused bicyclic hydrocarbon-C₁₋₄ alkyl group,C₉₋₁₀ partly saturated and fused bicyclic hydrocarbon-C₂₋₄ alkenylgroup, C₆₋₁₀ aryl group and C₇₋₁₄ aralkyl group, or an optionallysubstituted 5- to 7-membered aromatic or non-aromatic heterocyclic grouphaving 1-4 hetero atoms selected from nitrogen atom, oxygen atom andsulfur atom or R^(22c) and R^(23c) may be combined to form a C₃₋₇ carbonring, or (b) R^(20c) is H or an optionally substituted hydrocarbon groupselected from C₁₋₈ saturated aliphatic hydrocarbon group, C₂₋₈unsaturated aliphatic hydrocarbon group, C₃₋₇ saturated alicyclichydrocarbon group, C₃₋₇ unsaturated alicyclic hydrocarbon group, C₉₋₁₀partly saturated and fused bicyclic hydrocarbon group, C₃₋₇ saturated orunsaturated alicyclic-C₁₋₈ saturated or unsaturated aliphatichydrocarbon group, C₉₋₁₀ partly saturated and fused bicyclichydrocarbon-C₁₋₄ alkyl group, C₉₋₁₀ partly saturated and fused bicyclichydrocarbon-C₂₋₄ alkenyl group, C₆₋₁₀ aryl group and C₇₋₁₄ aralkylgroup; and R^(21c), R^(22c) and R^(23c) are the same or different andare an optionally substituted C₁₋₈ aliphatic hydrocarbon group, providedthat the sum total of the number of carbon atoms is 7 or more),

(iii) —NR^(20c)R^(25c) (wherein R^(20c) is as defined above and R^(25c)is an optionally substituted C₆₋₁₀ aryl-C₂₋₄ alkyl, C₆₋₁₀ aryloxy-C₂₋₄alkyl, C₆₋₁₀ arylamino-C₂₋₄ alkyl, C₇₋₁₄ aralkylamino-C₂₋₄ alkyl, 5- to7-membered heterocyclic ring (having 1-4 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom)-C₂₋₄ alkyl or 5- to7-membered heterocyclic group having 1-4 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom),

(iv) a substituted 5- to 7-membered cyclic amino group (e.g.,piperidino, piperdino, morpholino, thiomorpholino, etc.), or

(v) —OR^(24c) (wherein R^(24c) is (a) an optionally substituted C₇₋₁₄aralkyl group, (b) an optionally substituted C₃₋₇ alicyclic hydrocarbongroup, (c) an optionally substituted C₇₋₂₄ aliphatic hydrocarbon group,or (d) an optionally substituted 5- to 7-membered aromatic ornon-aromatic heterocyclic group having 1-4 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom;

wherein said substituents for R^(1a), Z^(2c), R^(20c), R^(21c), R^(22c),R^(23c), R^(24c) and R^(25c) are 1 to 3 substituents selected from thegroup consisting of

-   -   1) C₁₋₆ alkyl,    -   2) C₂₋₆ alkenyl,    -   3) C₂₋₆ alkynyl,    -   4) C₃₋₇ cycloalkyl,    -   5) C₆₋₁₀ aryl which may be substituted with 1 to 3 substituents        selected from the group consisting of C₁₋₆ alkyl, amino, N—(C₁₋₆        alkyl)amino, N,N-di-(C₁₋₆ alkyl)amino, amidino, carbamoyl,        N—(C₁₋₆ alkyl)carbamoyl, N,N-di-(C₁₋₆ alkyl)carbamoyl,        sulfamoyl, N—(C₁₋₆ alkyl)sulfamoyl, N,N-di-(C₁₋₆        alkyl)sulfamoyl, carboxyl, C₂₋₇ alkoxycarbonyl, hydroxyl, C₁₋₆        alkoxy, mercapto, C₁₋₆ alkylthio, sulfo, cyano, azido, halogen,        nitro, nitroso, phosphono, C₁₋₆ alkoxyphosphoryl, di-(C₁₋₆        alkoxy)phosphoryl and C₁₋₆ alkyl substituted with phosphono,        C₁₋₆ alkoxyphosphoryl and di-(C₁₋₆ alkoxy)phosphoryl        (hereinafter the group of 5) is referred to as group “C”),    -   6) aromatic heterocyclic group selected from (a) aromatic 5- or        6-membered heterocyclic group having 1-4 hetero atoms selected        from nitrogen atom, oxygen atom and sulfur atom, (b) fused        bicyclic heterocyclic group formed by condensation of an        aromatic 5- or 6-membered heterocyclic group having 1 to 3        hetero atoms selected from nitrogen atom, oxygen atom and sulfur        atom with benzene ring or an aromatic 5- or 6-membered        heterocyclic group having 1 to 3 hetero atoms selected from        nitrogen atom, oxygen atom and sulfur atom and (c) fused        tricyclic heterocyclic group formed by condensation of [1] an        aromatic 5- or 6-membered heterocyclic group having 1-3 hetero        atoms selected from nitrogen atom, oxygen atom and sulfur atom,        [2] benzene ring, and [3] an aromatic 5- or 6-membered        heterocyclic group having 1-3 hetero atoms selected from        nitrogen atom, oxygen atom and sulfur atom or benzene ring,    -   7) heterocyclic-oxy group formed by combining each of the above        aromatic heterocyclic groups (a), (b) and (c) with oxy group,    -   8) non-aromatic 4- or 7-membered heterocyclic group having 1 to        3 hetero atoms selected from nitrogen atom, oxygen atom and        sulfur atom,    -   9) C₇₋₁₄ aralkyl which may be substituted with 1 to 3        substituents selected from the group “C”,    -   10) amino group,    -   11) N-mono-substituted amino selected from N—(C₁₋₆ alkyl)amino,        N—(C₂₋₆ alkenyl)amino, N—(C₃₋₇ cycloalkyl)amino group and        N—(C₆₋₁₀ aryl)amino which may be substituted with 1 to 3        substituents selected from the group “C”,    -   12) amino substituted with two substituents selected from C₁₋₆        alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkenyl and C₆₋₁₀ aryl which may        be substituted with 1 to 3 substituents selected from the group        “C”,    -   13) amidino,    -   14) acyl selected from C₂₋₈ alkanoyl, C₃₋₈ alkenoyl, C₃₋₇        cycloalkyl-carbonyl, C₃₋₇ cycloalkenyl-carbonyl, C₆₋₁₀        aryl-carbonyl which may be substituted with 1 to 3 substituents        selected from the group “C”, and heterocyclic-carbonyl formed by        binding of an aromatic or non-aromatic 5- or 6-membered        heterocyclic group having 1-3 hetero atoms selected from        nitrogen atom, oxygen atom and sulfur atom with carbonyl,    -   15) carbamoyl,    -   16) mono-substituted carbamoyl group selected from N—(C₁₋₆        alkyl)carbamoyl, N—(C₂₋₆ alkenyl)carbamoyl, N—(C₃₋₇        cycloalkyl)carbamoyl and N—(C₆₋₁₀ aryl)carbamoyl which may be        substituted with 1 to 3 substituents selected from the group        “C”,    -   17) carbamoyl substituted with two substituents selected from        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl and C₆₋₁₀ aryl which        may be substituted with 1 to 3 substituents selected from the        group “C”,    -   18) sulfamoyl,    -   19) N-mono-substituted sulfamoyl selected from N—(C₁₋₆        alkyl)sulfamoyl, N—(C₂₋₆ alkenyl)sulfamoyl, N—(C₃₋₇        cycloalkyl)sulfamoyl and N—(C₆₋₁₀ aryl)sulfamoyl which may be        substituted with 1 to 3 substituents selected from the group        “C”,    -   20) sulfamoyl substituted with two substituents selected from        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl and C₆₋₁₀ aryl which        may be substituted with 1 to 3 substituents selected from the        group “C”,    -   21) carboxyl,    -   22) C₁₋₆ alkoxy-carbonyl,    -   23) hydroxyl,    -   24) C₁₋₆ alkoxy,    -   25) C₂₋₁₀ alkenyloxy,    -   26) C₃₋₇ cycloalkyloxy,    -   27) C₆₋₁₀ aryloxy which may be substituted with 1 to 3        substituents selected from the group “C”,    -   28) C₇₋₁₄ aralkyloxy which may be substituted with 1 to 3        substituents selected from the group “C”,    -   29) mercapto,    -   30) C₁₋₆ alkylthio,    -   31) C₇₋₁₄ aralkylthio which may be substituted with 1 to 3        substituents selected from the group “C”,    -   32) C₆₋₁₀ arylthio which may be substituted with 1 to 3        substituents selected from the group “C”,    -   33) C₁₋₆ alkylsulfinyl,    -   34) C₇₋₁₄ aralkylsulfinyl which may be substituted with 1 to 3        substituents selected from the group “C”,    -   35) C₆₋₁₀ arylsulfinyl which may be substituted with 1 to 3        substituents selected from the group “C”,    -   36) C₁₋₆ alkylsulfonyl,    -   38) C₇₋₁₄ aralkylsulfonyl which may be substituted with 1 to 3        substituents selected from the group “C”,    -   39) C₆₋₁₀ arylsulfonyl which may be substituted with 1 to 3        substituents selected from the group “C”,    -   40) sulfo,    -   41) cyano,    -   42) azido,    -   43) halogen,    -   44) nitro,    -   45) nitroso,    -   46) phosphono,    -   47) C₁₋₆ alkoxy-phosphoryl    -   48) di-C₁₋₆ alkoxy-phosphoryl,    -   49) C₁₋₆ alkyl substituted with phosphono, C₁₋₆ alkoxyphosphoryl        or di-(C₁₋₆ alkoxy)phosphoryl    -   50) C₁₋₆ alkyl substituted with 1 to 4 halogen atoms    -   51) C₁₋₆ alkoxy substituted with 1 to 4 halogen atoms and    -   52) C₁₋₆ alkylenedioxy        (hereinafter the group of above 1) to 52) is referred to as        group “B”).

Specific examples of these substituents include the same groups as thoseexemplified with respect to the substituents of the 5- to 7-memberedring of ring A.

As R^(1a) of the formula (IIIa), more preferred is the group representedby the formula: —CONR^(20c)(CR^(21c)R^(22c)R^(23c)) (wherein R^(20c),R^(21c), R^(22c) and R^(23c) are as defined above).

Further more preferably, R^(1a) is (1) a 5- to 7-membered aromaticheterocyclic group having 1-4 hetero atoms selected from nitrogen atom,oxygen atom and sulfur atom (e.g., 1,3,4-oxadiazolyl,1,3,4-thiadiazolyl, etc.) which is substituted with C₁₋₄ alkyl-C₇₋₁₄aralkyl (e.g., 1-ethyl-1-(4-methylphenyl)propyl, etc.), or (2) a grouprepresented by the formula: —CO-Z^(2c) (wherein Z^(2c′) is

(i) —NR^(21c′) (CR^(21c′)R^(22c′)R^(23c′)) (wherein (a) R^(20c′) is H orC₁₋₆ alkyl; R^(21c′) is a C₆₋₁₀ aryl group or a 5- to 7-memberedaromatic heterocyclic group having 1-4 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom, each of which may besubstituted with 1 to 3 substituents selected from the group consistingof halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, halogeno C₁₋₆ alkyl, hydroxy-C₁₋₆alkyl, C₁₋₆ alkoxy, carboxyl, C₁₋₆ alkoxy-carbonyl, C₁₋₆alkyl-carbonyloxy, C₁₋₆ alkyl-carbonyloxy-C₁₋₆ alkyl, carboxy-C₁₋₆alkoxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkyl, C₁₋₆ alkoxy-carbonyl-C₁₋₆alkoxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy-C₁₋₆ alkyl, carbonyl, C₁₋₆alkyl-carbonyl, amino, mono- or di-C₁₋₆ alkylamino, phenyl (said phenylmay be substituted with 1 to 3 substituents selected from halogen, C₁₋₆alkyl and halogeno C₁₋₆ alkyl) and a 5- to 7-membered aromaticheterocyclic group having 1-4 hetero atoms selected from nitrogen atom,oxygen atom and sulfur atom; R^(22c′) and R^(23c′) are the same ordifferent and are C₁₋₆ alkyl group, C₅₋₇ cycloalkyl group, phenyl group(said phenyl group may be substituted with 1 to 3 substituents selectedfrom C₁₋₆ alkyl, halogeno C₁₋₆ alkyl and C₁₋₆ alkoxy), C₁₋₆alkoxy-carbonyl-C₁₋₆ alkyl group or C₁₋₆ alkyl-carbonyl-C₂₋₆ alkenylgroup, or R^(22c′) and R^(23c′) may be combined each other to form aC₃₋₇ carbon ring; or (b) R^(20c′) and R^(21c′) are combined each otherto form a 5- to 7-membered ring and said ring may be substituted withC₁₋₆ alkoxy or C₇₋₁₄ aralkyl, and R^(22c′) and R^(23c′) are C₁₋₆ alkylgroup),

(ii) —NR^(20c′)R^(25c′) (wherein R^(20c′) is H or C₁₋₆ alkyl group;R^(25c′) is C₆₋₁₀ aryl-C₂₋₄ alkyl group, C₆₋₁₀ aryloxy-C₂₋₄ alkyl group,C₆₋₁₀ arylamino-C₂₋₄ alkyl group, C₇₋₁₄ aralkylamino-C₂₋₄ alkyl group,5- to 7-membered heterocyclic ring-C₂₋₄ alkyl group or 5- to 7-memberedheterocyclic group, each of which may be substituted with 1 or 2substituents selected from the group consisting of halogen, C₁₋₆ alkyl,C₆₋₁₀ aryl, C₁₋₆ alkoxy, amino, mono- or di-C₁₋₆ alkylamino, 5- to7-membered cyclic amino, hydroxy, oxo, C₁₋₆ alkoxy-carbonyl and cyano),or

(iii) a 5- to 7-membered cyclic amino group which is substituted with 1to 3 substituents selected from the group consisting of halogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₅₋₇ cycloalkyl, C₆₋₁₀ aryl(said aryl may have 1 or 2 substituents selected from halogen, C₁₋₆alkyl, halogeno C₁₋₆ alkyl and C₁₋₆ alkoxy), C₇₋₁₄ aralkyl (said aralkylmay have 1 or 2 substituents selected from halogen, C₁₋₆ alkyl, halogenoC₁₋₆ alkyl and C₁₋₆ alkoxy), hydroxy, hydroxy-C₁₋₆ alkyl, C₆₋₁₀ aryloxy(said aryloxy may have 1 or 2 substituents selected from halogen, C₁₋₆alkyl, halogeno C₁₋₆ alkyl and C₁₋₆ alkoxy), C₇₋₁₄ aralkyloxy, C₆₋₁₀aryl-carbonyl, carboxyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, C₆₋₁₀aryl-carbamoyl, amino, C₆₋₁₀ aryl-carbonylamino, C₁₋₆alkyl-carbonylamino, C₁₋₆ alkoxy-carbonylamino, C₆₋₁₀ arylthio, C₆₋₁₀arylsulfonyl, cyano, oxo and 5- to 7-membered heterocyclic group.).

R³ of the formulas (II), (III) and (IIIa) is H, an optionallysubstituted hydrocarbon group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above).

Examples of an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group and anoptionally substituted heterocyclic group of R³ include the same groupsas those exemplified with respect to the substituents of the 5- to7-membered ring of ring A.

R³ is preferably H, a C₁₋₆ alkyl group or a C₇₋₁₄ aralkyl group, andmore preferably R³ is H.

Y in the formulas (I), (II), (III) and (IIIa) is C, CR⁴, or N.

R⁴ is H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, cyano group, a halogen atom, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- and Z² are as defined above).

Examples of an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted heterocyclic group and halogen of R⁴ include thesame groups as those exemplified with respect to the substituents of the5- to 7-membered ring of ring A.

Y is preferably CH.

R⁸ of the formulas (III) and (IIIa) is H, an optionally substitutedhydrocarbon group, an optionally substituted hydroxyl group, anoptionally substituted amino group, an optionally substituted thiolgroup, cyano group, a halogen atom, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above).

Examples of an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, halogen atom and an optionallysubstituted heterocyclic group of R⁸ include the same groups as thoseexemplified with respect to the substituents of the 5- to 7-memberedring of ring A.

R⁸ is preferably H, a C₁₋₆ alkyl group, a C₁₋₆ alkylthio group or a C₁₋₆alkoxy group which may be substituted with hydroxyl group, and morepreferably R⁸ is H or a C₁₋₆ alkyl group.

Ar in the formulas (I), (II), (III) and (IIIa) is an optionallysubstituted cyclic group.

Examples of the optionally substituted cyclic group of Ar include anoptionally substituted aromatic or non-aromatic hydrocarbon ring groupor an optionally substituted aromatic or non-aromatic heterocyclicgroup, and the like.

Examples of the aromatic hydrocarbon ring group and the heterocyclicgroup of Ar include the same aromatic hydrocarbon group and heterocyclicgroup as exemplified with respect to the above substituents of the 5- to7-membered ring of ring A.

Examples of the non-aromatic hydrocarbon ring group include a saturatedalicyclic hydrocarbon group having 3-7 carbon atoms (e.g., cycloalkylgroup, etc.) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and the like; an unsaturated alicyclic hydrocarbon grouphaving 3-7 carbon atoms (e.g., cycloalkenyl group, cycloalkadienylgroup, etc.) such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl,1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl,2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl, etc.; a partlysaturated and fused bicyclic hydrocarbon group [preferably, C₉₋₁₀ partlysaturated and fused bicyclic hydrocarbon group, etc. (including thosewhere the benzene ring is combined to 5- or 6-membered non-aromaticcyclic hydrocarbon group)] such as 1-indenyl, 2-indenyl, 1-indanyl,2-indanyl, 1,2,3,4-tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl,1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1-naphthyl,1,4-dihydro-2-naphthyl, 3,4-dihydro-1-naphthyl, 3,4-dihydro-2-naphthyl,etc.; and the like.

Examples of the substituent of an optionally substituted aromatic ringgroup and an optionally substituted heterocyclic group of Ar include thesame groups as those exemplified with respect to the above substituentsof the 5- to 7-membered ring of ring A.

Ar is preferably (1) a C₆₋₁₀ aryl group, (2) a 5- to 7-membered aromaticor non-aromatic heterocyclic group having 1-4 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom, or (3) a C₃₋₇ saturated orunsaturated alicyclic hydrocarbon group, each of which may besubstituted with 1 to 3 substituents selected from the group “B”.

More preferably, Ar is a C₆₋₁₀ aryl group which may be substituted with1 to 3 substituents selected from the group “B”, a 5- to 7-memberedaromatic heterocyclic group having 1-4 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom which may be substituted with1 to 3 substituents selected from the group “B”, or a C₃₋₇ saturated orunsaturated alicyclic hydrocarbon group.

Further more preferably, Ar is (1) a C₆₋₁₀ aryl group (e.g., phenyl,naphthyl, etc.) which may be substituted with 1 or 2 substituentsselected from the group consisting of halogen atom, C₁₋₆ alkyl, C₁₋₆alkoxy, hydroxy, C₇₋₁₄ aralkyloxy and mono- or di-C₁₋₄ alkylamino, (2) a5- to 7-membered aromatic heterocyclic group having 1-4 hetero atomsselected from nitrogen atom, oxygen atom and sulfur atom (e.g., pyridyl,furyl, thiazolyl, thienyl, etc.) which may be substituted with C₁₋₄alkyl or (3) a C₅₋₇ cycloalkyl group (e.g., cyclohexyl etc.), and mostpreferably, Ar is an optionally halogenated phenyl group.

R⁹ and R¹⁰ of the formulas (II), (III) and (IIIa) are the same ordifferent and are H, an optionally substituted hydrocarbon group, anoptionally substituted hydroxyl group, an optionally substituted aminogroup, an optionally substituted thiol group, cyano group, a halogenatom, an optionally substituted heterocyclic group, or a group of theformula: -Z¹-Z² (wherein -Z¹- and Z² are as defined above), or R⁹ andR¹⁰ may be combined to form an oxo group, methylene group or a ring.

Examples of an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, a halogen atom and an optionallysubstituted heterocyclic group of R⁹ and R¹⁰ include the same groups asthose exemplified with respect to the above substituents of the 5- to7-membered ring of ring A.

One of R⁹ and R¹⁰ is preferably a hydrogen atom or C₁₋₆ alkyl groupwhich may be substituted with 1 to 3 substituents selected from thegroup “B” and the other is (1) a hydrocarbon group selected from C₁₋₈saturated aliphatic hydrocarbon group, C₂₋₈ unsaturated aliphatichydrocarbon group, C₃₋₇ saturated alicyclic hydrocarbon group, C₃₋₇unsaturated alicyclic hydrocarbon group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon group, C₃₋₇ saturated or unsaturatedalicyclic-C₁₋₈ saturated or unsaturated aliphatic hydrocarbon group,C₉₋₁₀ partly saturated and fused bicyclic hydrocarbon-C₁₋₄ alkyl group,C₉₋₁₀ partly saturated and fused bicyclic hydrocarbon-C₂₋₄ alkenylgroup, C₆₋₁₀ aryl group and C₇₋₁₄ aralkyl group, each of which may besubstituted with 1 to 3 substituents selected from the group “B” or (2)a 5- to 7-membered aromatic or non-aromatic heterocyclic group having1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfuratom, which may be substituted with 1 to 3 substituents selected fromthe group “B”, or

R⁹ and R¹⁰ may be combined to form a C₅₋₇ carbon ring.

More preferably, one of R⁹ and R¹⁰ is preferably a hydrogen atom or C₁₋₆alkyl group and the other is an optionally halogenated C₁₋₆ alkyl group,C₆₋₁₀ aryl group, C₇₋₁₀ aralkyl group or a 5- to 7-membered aromaticheterocyclic group, or R⁹ and R¹⁰ are a C₅₋₇ carbon ring formed bycombining together.

Examples of R¹¹ and R¹² of the formula (II) are the same or differentand are H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, cyano group, a halogen atom, anoptionally substituted heterocyclic group, or a group of the formula:-Z^(1′)-Z² (wherein -Z^(1′)- is —CS—, —SO— or —SO₂—, and Z² is asdefined above).

Examples of an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, a halogen atom and an optionallysubstituted heterocyclic group of R¹¹ and R¹² include the same groups asthose exemplified with respect to the above substituents of the 5- to7-membered ring of ring A.

R⁹ and R¹⁰, or R¹¹ and R¹² may be combined to form an oxo group,methylene group or a ring such as a C₃₋₆ saturated or unsaturated carbonring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl,2-cyclohexenyl, 3-cyclohexenyl, etc.); or R¹⁰ and R¹¹ may be combined toform a ring such as a C₃₋₆ saturated or unsaturated carbon ring (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclopentenyl,2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl,3-cyclohexenyl, etc.).

is a single bond or a double bond.

Z in the formula (I) is CR⁵, CR⁵R⁶, N or NR⁷, and CR⁵ is as definedabove.

R⁶ is H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, cyano group, a halogen atom, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- and Z² are as defined above)).

Examples of an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, and an optionally substitutedheterocyclic group of R⁶ include the same groups as those exemplifiedwith respect to the above substituents of the 5- to 7-membered ring ofring A.

R⁷ is H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, cyanogroup, a halogen atom, an optionally substituted heterocyclic group, ora group of the formula: -Z¹-Z² (wherein -Z¹- and Z² are as definedabove)).

Examples of an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, ahalogen atom and an optionally substituted heterocyclic group of R⁷include the same groups as those exemplified with respect to the abovesubstituents of the 5- to 7-membered ring of ring A.

R⁵, R⁶ and R⁷ may be the same or different.

R⁵ is H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, an optionally substituted sulfonylgroup or an optionally substituted sulfinyl group.

Examples of an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, an optionally substituted sulfonylgroup and an optionally substituted sulfinyl group of R include the samegroups as those exemplified with respect to the above substituents ofthe 5- to 7-membered ring of ring A.

R and Z may be combined to form a ring B

Ring B in the formula (I) is an optionally substituted 5- to 7-memberedheterocyclic ring and examples thereof include the same group as thatexemplified with respect to the 5- to 7-membered ring of ring A.

X² of the formula (I) is N or NR³ and R³ are as defined above.

X³ of the formula (III) and (IIIa) is a bond, oxygen atom, an optionallyoxidized sulfur atom, N, NR^(7′), or an optionally substituted bivalentC₁₋₂ hydrocarbon group.

R^(7′) is H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted heterocyclic group, or a group of the formula-Z^(1′)-Z² (wherein -Z^(1′)- is —CS—, —SO— or —SO₂—, and Z² is asdefined above)).

Examples of an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, andan optionally substituted heterocyclic group of R^(7′) include the samegroups as those exemplified with respect to the substituents of the 5-to 7-membered ring of ring A.

Examples of an optionally substituted bivalent C₁₋₂ hydrocarbon groupinclude —CH₂—, —(CH₂)₂—, —CH═CH— and the like which may be substitutedwith one or two substituents selected from those exemplified withrespect to the substituents of the 5- to 7-membered ring of ring A.

In the formula (IIIa), X³ is preferably CH₂.

Preferred compounds of the formula (I) include not only the compounds ofthe formula (IIIa) but also the other compounds wherein -Z¹- is —CO— andZ² is an optionally substituted hydroxyl group (e.g., hydroxy, C₁₋₆alkoxy, etc.) or amino group which is substituted with an optionallysubstituted phenyl group or an optionally substituted condensed phenylgroup (e.g., phenylamino, 3,5-dimethoxyphenylamino, 3-biphenylylamino,2,3-dihydro-1H-inden-5-yl-amino, quinolin-6-yl-amino, etc.).

In the formula (II),

(1) when ring A is a 6-membered ring and Q is C or CR⁵, X¹ is C-Z¹-Z²,C(-Z¹-Z²)R² or N-Z¹-Z², and both R⁹ and R¹⁰ are not H, or R⁹ and R¹⁰ arenot combined to form an oxo group, or R¹⁰ and R¹¹ are not combined toform a 5-membered ring;(2) when ring A is a 6-membered ring and Q is N, X¹ is C-Z¹-Z²,C(-Z¹-Z²)R² or N-Z¹-Z², and R⁹ and R¹⁰ are not combined to form an oxogroup;(3) when ring A is a 5-membered ring and Q is C or CR⁵, X¹ is C-Z¹-Z²,C(-Z¹-Z²)R² or N-Z¹-Z², and Z² is an optionally substituted amino group;and(4) when ring A is a 5-membered ring and Q is N, at least one of R⁹ andR¹⁰ is CHR¹⁵R¹⁶ (wherein R¹⁵ and R¹⁶ are the same or different and areH, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, a halogen atom, an optionallysubstituted heterocyclic group, or a group of the formula: -Z¹-Z²(wherein -Z¹- and Z² are as defined above).

Examples of an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, a halogen atom and an optionallysubstituted heterocyclic group include the same groups as thoseexemplified with respect to the above substituents of the 5- to7-membered ring of ring A.

In the formulas (II) and (III), preferably, R¹ is a group of theformula: -Z¹-Z²; Z¹ is —CO— and Z² is an optionally substituted hydroxylgroup or an optionally substituted amino group; Ar is an optionallysubstituted aromatic ring group; and both R⁹ and R¹⁰ are the same ordifferent and are C₁₋₆ alkyl groups or R⁹ and R¹⁰ are combined to form aring such as a saturated or unsaturated C₃₋₆ ring as described above.

In the formula (III), preferably, R³ is H. More preferably, in theformula (III), R¹ is a group of the formula: -Z¹-Z² (wherein -Z¹- is—CO—, —CS—, —SO— or —SO₂—, and Z² is an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, anoptionally substituted hydroxyl group, or an optionally substitutedamino group); R³ is H; Ar is an optionally substituted aromatic ringgroup; X³ is CR¹¹R¹² (wherein R¹¹ and R¹² are the same or different andare H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, cyano group, a halogen atom, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- and Z² are as defined above), or R¹¹ and R¹² may becombined to form an oxo group, methylene group or a ring such as asaturated or unsaturated C₃₋₆ ring as described above); and R⁹ and R¹⁰are the same or different and are a C₁₋₆ alkyl group, or R⁹ and R¹⁰ maybe combined to form a ring such as a saturated or unsaturated C₃₋₆ ringas described above.

As for a salt of the compound of formula (I), (II), (III) or (IIIa)(hereinafter sometimes referred to as Compound (I), (II), (III) or(IIIa)), a pharmaceutically acceptable salt is preferred. Examplesthereof include a salt with an inorganic base, a salt with an organicbase, a salt with an inorganic acid, a salt with an organic acid, a saltwith a basic or acidic amino acid, or the like. Preferred examples of asalt with an inorganic base include an alkali metal salt such as sodiumsalt, potassium salt, or the like; an alkaline earth metal salt such ascalcium salt, magnesium salt, or the like; and aluminum salt; ammoniumsalt; or the like. Preferred examples of a salt with an organic baseinclude a salt with trimethylamine, triethylamine, pyridine, picoline,ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, or the like. Preferred examples of a saltwith an inorganic acid include a salt with hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or thelike. Preferred examples of a salt with an organic acid include a saltwith formic acid, acetic acid, trifluoroacetic acid, fumaric acid,oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid,malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, or the like. Preferred examples of a salt with abasic amino acid include a salt with arginine, lysine, ornithine or thelike. Preferred examples of a salt with an acidic amino acid include asalt with aspartic acid, glutamic acid, or the like.

Compound (I), (II), (III) or (IIIa) may be in the form of a prodrugthereof. The prodrug of Compound (I), (II), (III) or (IIIa) refers to acompound that is converted into Compound (I), (II), (III) or (IIIa) by areaction with an enzyme, gastric acid, or the like under a physiologicalcondition in the living body, namely, (i) a compound that is convertedinto Compound (I), (II), (III) or (IIIa) by an enzymatic oxidation,reduction, hydrolysis, or the like, and (ii) a compound that isconverted into Compound (I), (II), (III) or (IIIa) by hydrolysis withgastric acid or the like. Examples of a prodrug of Compound (I), (II),(III) or (IIIa) to be used include a compound or its salt whereinhydroxyl group in Compound (I), (II), (III) or (IIIa) is acylated,alkylated, phosphorylated, or converted into borate (e.g., a compound orits salt wherein hydroxyl group in Compound (I), (II), (III) or (IIIa)is converted into acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy,succinyloxy, fumaryloxy, alanyloxy, dimethylaminomethylcarbonyloxy,etc.), a compound or its salt wherein carboxyl group in Compound (I),(II), (III) or (IIIa) is esterified or amidated (e.g., a compound or itssalt wherein carboxyl group in Compound (I), (II), (III) or (IIIa) issubjected to ethyl esterification, phenyl esterification,carboxyoxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methylesterification, cyclohexyloxycarbonyl esterification, or conversion intothe methyl amide, etc.), or the like. These prodrugs can be producedaccording to a per se known method or its modified method.

Further, a prodrug of Compound (I), (II), (III) or (IIIa) may be acompound or its salt that is converted into Compound (I), (II), (III) or(IIIa) under physiological conditions as described in “Development ofDrugs”, Volume 7, Molecular Design, Hirokawa Shoten, 1990; pages163-198.

Compound (I), (II), (III) or (IIIa) may be labeled with an isotope (forexample, ²H, ³H, ¹⁴C, ³⁵S, ¹²⁵I, or the like) or the like.

When the compound obtained by the present invention or a salt thereofhas a double bond in its molecule and a steric configuration of Z or Eexists, each of the stereoisomers and a mixture thereof are included inthe present invention.

When a steric configuration exists due to an asymmetric carbon in themolecule of the compound obtained by the present invention or a saltthereof, each of them and a mixture thereof are included in the presentinvention.

Hereinafter, production of the compound of the present invention will beillustrated.

A process for preparing Compound (II), Compound (III) and Compound(IIIa) of the present invention will be shown in the following schemes 1to 13.

A compound wherein Q is N, and Y is C or CR⁴ in Compound (II) can beprepared according to the schemes 1 to 3.

A compound wherein Q is C, and Y is C or CR⁴ in Compound (II) can beprepared according to the scheme 4.

A compound wherein Q is N, and Y is N in Compound (II) can be preparedaccording to the scheme 5.

A compound wherein Y is C or CR⁴ in Compound (III) and Compound (IIIa)can be prepared by the scheme 6.

A compound wherein Y is N in Compound (III) and Compound (IIIa) can beprepared by the scheme 7.

A compound wherein Q is C, and Y is N in Compound (II) can be preparedby the scheme 13.

wherein A-1 is the same as A, and the other symbols are as definedabove.

In step A, Compound (II-1) is prepared by cyclization reaction ofCompound (IV-1) and Compound (X) with an acid or a base. Examples of theacid used in this reaction include: inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid and phosphoric acid; organic acidssuch as acetic acid, trifluoroacetic acid, methanesulfonic acid,benzenesulfonic acid and p-toluenesulfonic acid; and Lewis acids such aszinc (II) chloride, tin (IV) chloride, aluminium chloride and the like.

Examples of the base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium bicarbonate and potassium carbonate;amines such as pyridine, triethylamine, N,N-dimethylaniline and1,8-diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassiumhydride and sodium hydride; and alkali metal alkoxides such as sodiummethoxide, sodium ethoxide and potassium t-butoxide.

An amount of these acids or bases to be used is preferably about 0.1 toabout 5 mole equivalent relative to Compound (IV-1).

Examples of a solvent having no adverse effect on the reaction includearomatic hydrocarbons such as benzene, toluene and xylene; ethers suchas tetrahydrofuran, dimethoxyethane, dioxane and diethyl ether; amidessuch as N,N-dimethylformamide; alcohol such as ethanol, propanol,tert-butanol and methoxyethanol; and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio.

A reaction temperature is usually about −50° C. to about 200° C.,preferably about −10° C. to about 150° C.

A reaction time is usually about 0.5 to about 60 hours.

The thus obtained compound (II-1) can be isolated and purified by theknown separating and purifying methods, for example, concentration,concentration under the reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

Compound (IV-1) used herein can be prepared, for example, according tothe method described in Bilestein, vol. 25, p. 2033. In addition,Compound (X) can be prepared, for example, according to Organometallics,vol. 11, p. 954.

In step B, Compound (II-2) is prepared by a reduction reaction forCompound (II-1).

In the present reaction, a catalytic hydrogenation method usingpalladium carbon, palladium hydroxide or the like, or reduction using areducing agent is performed. As the reducing agent, sodium borohydride,aluminium lithium hydride and lithium borohydride are used. In thepresent reaction, if needed, any solvents can be used as long as they donot inhibit the reaction. Inter alia, alcohols (e.g. C₁₋₃ alcohol suchas methanol, ethanol, propanol and the like) or ethers (diethyl ether,diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran,dioxane etc.) are preferable.

A reaction time is usually about 0.5 to about 20 hours.

The thus obtained Compound (II-2) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under the reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

wherein A-1 is the same as A, and the other symbols are as definedabove.

In step C, Compound (V) is prepared by a reaction for cyclizing Compound(IV-1) and Compound (XI). The present reaction is carried out in thepresence of an acid in a solvent having no adverse effect on thereaction or without a solvent according to the conventional method.

Examples of the acid include inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid and phosphoric acid; organic acids suchas acetic acid, trifluoroacetic acid, methanesulfonic acid,benzenesulfonic acid and p-toluenesulfonic acid; Lewis acids such aszinc (II) chloride, tin (IV) chloride, aluminium chloride and the like.

An amount of these acids is preferably about 0.1 to about 5 moleequivalent relative to Compound (IV-1).

Examples of the solvent having no adverse effect on the reaction includearomatic hydrocarbons such as benzene, toluene and xylene; ethers suchas tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbonssuch as chloroform and dichloromethane; amides such asN,N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. Thesesolvents may be used by mixing at an appropriate ratio.

A reaction temperature is usually about −50° C. to 150° C., preferablyabout −10° C. to about 120° C.

A reaction time is usually about 0.5 to about 20 hours.

The thus obtained Compound (V) can be isolated and purified by the knownisolating and purifying methods, for example, concentration,concentration under the reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

In step B, Compound (II-3) can be prepared according to step B in thescheme 1.

wherein Y′ is C or CR⁴, and L and L′ is a leaving group, and L is morereactive than L′, and the other symbols are as defined above.

In step D, Compound (VI-1) is prepared from Compound (IV-1). The presentmethod is carried out in the presence of a base in a solvent having noadverse effect on the reaction according to the conventional method.Specific examples of leaving groups L and L′ include halogen atom,sulfonyloxy group such as p-toluenesulfonyloxy group, methanesulfonyloxygroup and trifluoromethanesulfonyloxy group, and acyloxy group such asacetyloxy group and benzoyloxy group.

Example of the base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium bicarbonate and potassium carbonate;amines such as pyridine, triethylamine, N,N-dimethylaniline and1,8-diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassiumhydride and sodium hydride; and alkali metal alkoxides such as sodiummethoxide, sodium ethoxide and potassium t-butoxide.

An amount of these bases to be used is preferably about 1 to about 5mole equivalent relative to Compound (IV).

Examples of the solvent having no adverse effect on the reactioninclude: aromatic hydrocarbon such as benzene, toluene and xylene;ethers such as tetrahydrofuran, dioxane and diethyl ether; amides suchas N,N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide.These solvents may be used by mixing at an appropriate ratio.

A reaction temperature is usually about −50 to about 150° C., preferablyabout −10° C. to about 120° C.

A reaction time is usually about 0.5 about 20 hours.

The thus obtained Compound (VI-1) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under the reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

In step E, Compound (II-4) is prepared by an intramolecular cyclizationreaction of Compound (VI-1). The present method is carried out in thepresence of an acid or a base in a solvent having no adverse effect onthe reaction according to the conventional method. Specific example of aleaving group L′ include halogen atom, p-toluenesulfonyloxy group,methanesulfonyloxy group and trifluoromethanesulfonyloxy group.

Examples of the acid include inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid and phosphoric acid; organic acids suchas acetic acid, trifluoroacetic acid, methanesulfonic acid,benzenesulfonic acid and p-toluenesulfonic acid; and Lewis acids such aszinc (II) chloride, tin (IV) chloride, aluminium chloride and the like.Examples of the base include: alkali metal salts such as potassiumcarbonate; amines such as pyridine, triethylamine, N,N-dimethylanilineand 1,8-diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassiumhydride and sodium hydride; and alkali metal alkoxides such as sodiummethoxide, sodium ethoxide and t-butoxide.

An amount of these acids or bases to be used is preferably about 1 toabout 5 mole equivalent relative to Compound (IV-1).

Examples of the solvent having no adverse effect on the reaction includearomatic hydrocarbons such as benzene, toluene and xylene; ethers suchas tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbonssuch as chloroform and dichloromethane; amides such asN,N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. Thesesolvents may be used by mixing at an appropriate ratio.

A reaction temperature is usually about −50° C. to about 150° C.,preferably about −10° C. to about 120° C.

A reaction time is usually about 0.5 to about 20 hours.

The thus obtained Compound (II-4) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under the reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

wherein A-2 is the same as A, and the other symbols are as definedabove.

In step F, Compound (VI-2) is prepared from Compound (IV-2) and Compound(XII). The present method is carried out in the presence of a base in asolvent having no adverse effect on the reaction according to theconventional method.

Examples of the base include: alkali metal salts such as potassiumcarbonate, sodium carbonate and cesium carbonate; amines such aspyridine, triethylamine, N,N-dimethylaniline and1,8-diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassiumhydride and sodium hydride; and alkali metal alkoxides such as sodiummethoxide, sodium ethoxide and potassium t-butoxide.

An amount of these bases to be used is preferably about 1 to about 5mole equivalent relative to Compound (IV-2).

Examples of the solvent having no adverse effect on the reaction includearomatic hydrocarbons such as benzene, toluene and xylene; ethers suchas tetrahydrofuran; dioxane and diethyl ether; halogenated hydrocarbonssuch as chloroform and dichloromethane; amides such asN,N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. Thesesolvents may be used by mixing at an appropriate ratio.

A reaction temperature is usually about −50° C. to about 200° C.,preferably about −10° C. to about 150° C.

A reaction time is usually about 0.5 to about 20 hours.

The thus obtained Compound (VI-2) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under the reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

In step G, Compound (II-5) is prepared by a reaction for reducingCompound (VI-2).

In the present reaction, a catalytic hydrogenation method usingpalladium carbon, palladium hydroxide or Raney nickel, or reductionusing a reducing agent is carried out. As the reducing agent, sodiumborohydride, aluminium lithium hydride and lithium borohydride are used.In the present reaction, if needed, any solvents can be used as long asthey do not inhibit the reaction. Inter alia, alcohols (e.g. C₁₋₃alcohol such as methanol, ethanol, propanol and the like) or ethers(diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether,tetrahydrofuran, dioxane etc.) are preferable.

A reaction time is usually about 0.5 to 20 hours.

The thus obtained Compound (II-5) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under the reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

wherein Ar¹ is an optionally substituted non-aromatic hydrocarbon ringor an optionally substituent non-aromatic heterocyclic ring, Ar² is anoptionally substituted aromatic hydrocarbon ring or an optionallysubstituted aromatic heterocyclic ring, and A-3 is the same as A, andthe other symbols are as defined above.

In step H, an amino group of Compound (IV-3) is converted into adiazonium salt, and ylide is reacted thereon to prepare Compound(VIII-1). Diazotization in the present method is carried out in thepresence of an acid in a solvent having no adverse effect on thereaction according to the conventional method. As the acid, for example,acetic acid and hydrochloric acid are used. As a diazotizing agent,sodium nitrite, alkyl nitrite or sulfated nitrosyl is used.

As the solvent, water, dioxane, tetrahydrofuran and the like are used.

A reaction temperature is usually about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

A reaction time is usually about 0.5 to about 20 hours.

The thus obtained diazonium salt of Compound (IV-3) is reacted withylide produced from Compound (XIII-1) to prepare Compound (VIII-1). Thepresent step is carried out in the presence of a base in a solventhaving no adverse effect on the reaction. Examples of the base include:alkali metal salts such as potassium carbonate; amines such as pyridine,triethylamine, N,N-dimethylaniline and 1,8-diazabicyclo[5,4,0]undec-7-ene; metal hydrides such as potassium hydride and sodiumhydride; and alkali metal alkoxides such as sodium methoxide, sodiumethoxide and potassium t-butoxide.

An amount of these bases to be used is preferably about 1 to about 3mole equivalent relative to Compound (XIII-1).

Examples of the solvent having no adverse effect on the reaction includearomatic hydrocarbons such as benzene, toluene and xylene; ethers suchas tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbonssuch as chloroform and dichloromethane; amides such asN,N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. Thesesolvents may be used by mixing at an appropriate ratio.

Since the thus obtained Compound (VIII-1) is unstable depending on akind of the compound, it is used in the next step without isolation andpurification.

In step I, a reduction reaction of Compound (VIII-1) is carried out toprepare Compound (IX-1). In the present reaction, a catalytichydrogenation method using platinum oxide, Raney nickel, palladiumcarbon or palladium hydroxide, or reduction using a reducing agent isused. As the reducing agent, sodium borohydride, aluminium lithiumhydride and lithium borohydride are used. In the present reaction, ifneeded, any solvents can be used as long as they do not inhibit thereaction. Inter alia, alcohols (e.g. C₁₋₃ alcohol such as methanol,ethanol, propanol etc.) or ethers (diethyl ether, diisopropyl ether,ethylene glycol dimethyl ether, tetrahydrofuran, dioxane etc.) arepreferable.

A reaction time is usually about 0.5 to about 20 hours.

The thus obtained Compound (IX-1) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under the reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

In step J, Compound (II-7) is prepared by a reductive amination reactionbetween Compound (IX-1) and ketone (XV). The present method is carriedout in the presence of a reducing agent in a solvent having no adverseeffect on the reaction. Examples of the reducing agent include sodiumborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride andlithium borohydride. Although alcohol solvents such as ethanol andmethanol, dichloromethane, chloroform and carbon tetrachloride are usedas a solvent, any solvents can be used as long as they do not inhibitthe reaction.

The thus obtained Compound (II-7) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under the reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

In step K, a bismuth regent is acted on Compound (IX-1) to prepareCompound (II-8). The present method is carried out in the presence of ametal catalyst in a solvent having no adverse effect on the reaction. Asthe metal catalyst, for example, copper catalysts such as copper (II)acetate and copper (II) pivalate are used. Although dichloromethane,chloroform and carbon tetrachloride are used as a solvent, any solventscan be used as long as they do not inhibit the reaction.

A reaction temperature is usually about −80° C. to about 150° C.,preferably about −80° C. to about 100° C.

A reaction time is usually about 0.5 to about 20 hours.

The thus obtained Compound (II-8) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under the reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

wherein X⁴ is the same as X³, and the other symbols are as definedabove.

Step D and step E can be carried out according to step D and step E ofthe scheme 3, respectively, to prepare Compound (III-1).

wherein Ar³ is an optionally substituted hydrocarbon ring, an optionallysubstituted non-aromatic heterocyclic ring, an aromatic hydrocarbon ringor an aromatic heterocyclic ring, X⁵ is the same as X³, and otherrespective symbols have the same meanings as described above.)

Step H, step I, step J and step K can be carried out according to stepH, step I, step J, and step K of the scheme 5, respectively, to prepareCompound (III-2).

In Compound (II), when X¹ is C—COOR¹⁶, it can be converted as follows:

wherein A-4 denote the same meaning as that of A, R¹⁶ denotes anoptionally substituted carbon atom, and the other symbols are as definedabove.

In step L, Compound (II-10) is prepared by a reaction for leaving acarboxyl-protecting group.

All conventional methods used in a reaction for leaving acarboxyl-protecting group, for example, hydrolysis, reduction andelimination using a Lewis acid can be applied to the present reaction.It is preferable that hydrolysis is carried out in the presence of abase or an acid. Examples of the suitable base include inorganic basessuch as alkali metal hydroxide (e.g. sodium hydroxide and potassiumhydroxide), alkaline earth metal hydroxide (e.g. magnesium hydroxide andpotassium hydroxide), alkali metal carbonate (e.g. sodium carbonate andpotassium carbonate), alkaline earth metal carbonate (e.g. magnesiumcarbonate and calcium carbonate), alkali metal bicarbonate (e.g. sodiumbicarbonate and potassium bicarbonate), alkali metal acetate (e.g.sodium acetate and potassium acetate), alkaline earth metal phosphate(e.g. magnesium phosphate and calcium phosphate) and alkali metalhydrogen phosphate (e.g. disodium hydrogen phosphate and dipotassiumhydrogen phosphate), and organic bases such as trialkylamine (e.g.trimethylamine and triethylamine), picoline, N-methylpyrrolidine,N-methylmorpholine, 1,5-diazabicyclo[4.3.2]non-5-ene,1,4-diazabicyclo[2.2.2]non-5-ene and 1,8-diazabicyclo[4.3.0]-7-undecene.Hydrolysis using a base is carried out in water or a hydrophilic organicsolvent or a mixed solvent in many cases. Examples of the suitable acidinclude formic acid, hydrobromic acid and sulfuric acid.

The present hydrolysis reaction is usually carried out in an organicsolvent, water or a mixed solvent thereof. A reaction temperature is notparticularly limited, but is appropriately selected depending on a kindof a carboxyl-protecting group and an elimination method. Eliminationusing a Lewis acid is carried out by reacting Compound (II-9) or a saltthereof with a Lewis acid, for example, trihalogenated boron (e.g. borontrichloride and boron trifluoride), tetrahalogenated titanium (e.g.titanium tetrachloride and titanium tetrabromide), and halogenatedaluminium (e.g. aluminium chloride and aluminium bromide), or an organicacid (e.g. trichloroacetic acid and trifluoroacetic acid). Thiselimination reaction is preferably carried out in the presence of acation scavenger (e.g. anisole and phenol) and is usually carried out ina solvent such as nitroalkane (e.g. nitromethane and nitroethane),alkylene halide (e.g., methylene chloride and ethylene chloride),diethyl ether, carbon disulfide, and a solvent having no adverse effecton the reaction. These solvents may be used as a mixture thereof.

It is preferable that elimination by reduction is applied to eliminationof a protecting group such as halogenated alkyl (e.g. 2-iodoethyl and2,2,2-trichloroethyl)ester, and aralkyl (e.g. benzyl)ester. Examples ofa reduction method using in the present elimination reaction include theconventional catalytic reduction in the presence of a combination of ametal (e.g. zinc and zinc amalgam) or a salt of a chromium compound(e.g. chromate chloride and chromate acetate) and an organic orinorganic acid (e.g. acetic acid, propionic acid and hydrochloric acid);or the conventional metal catalyst (e.g. palladium carbon and Raneynickel). A reaction temperature is not particularly limited, but areaction is carried out under cooling, at room temperature of underwarming.

The thus obtained Compound (II-10) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under the reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

wherein R¹⁷ and R¹⁸ are optionally substituted alkyl group, allyl groupor hydroxy group; or R¹⁷ and R¹⁸ may be combined each other to form aring, Y″ is the same as Y, and the other symbols are as defined above.

In the present method, Compound (II-12) is prepared by reacting Compound(II-11) or a reactive derivative at a carboxyl group thereof and a saltthereof with the above Compound (XVI) or a reactive derivative at anamino group thereof or a salt thereof. Examples of the suitable reactivederivative at an amino group of Compound (XVI) include: Schiff base typeimino produced by a reaction of Compound (XVI) with a carbonyl compoundsuch as aldehyde, ketone and the like; silyl derivative produced by areaction of Compound (XVI) and a silyl compound such asbis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide,bis(trimethylsilyl)urea and the like; derivative produced by a reactionof Compound (XVI) with phosphorus trichloride or phosgene.

Specific examples of the suitable reactive derivative at a carboxylgroup of Compound (II-11) include acid halide, acid anhydride, activatedamide, activated ester and the like. Examples of the suitable reactivederivative include: acid chloride; acid azide; mixed acid anhydride withan acid such as substituted phosphoric acid such as dialkylphosphoricacid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoricacid, halogenated phosphoric acid and the like, dialkylphosphorous acid,sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid such asmethanesulfonic acid and the like, aliphatic carboxylic acid such asacetic acid, propionic acid, butyric acid, isobutyric acid, pivalicacid, pentanoic acid, isopentanoic acid, trichloroacetic acid and thelike or aromatic carboxylic acid such as benzoic acid and the like;symmetric acid anhydride; activated amide with imidazole; 4-substitutedimidazole, dimethylpyrazole, triazole or tetrazole; activated ester suchas cyanomethylester, methoxymethyl ester, dimethylaminomethyl ester,vinyl ester, propargyl ester, p-nitrophenyl ester, trichlorophenylester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenylester, phenyl thioester, p-nitrophenyl ester, p-cresyl thioester,carboxylmethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester,8-quinolyl thioester and the like, or esters with N-hydroxy compoundsuch as N,N-dimethylhydroxyamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazoleand the like. These reactive derivatives can be arbitrarily selecteddepending on a kind of Compound (II-11) to be used. Examples of thesuitable reactive derivative of Compound (II-12) include alkali metalsalts such as sodium salt, potassium salt and the like, alkaline earthmetal salts such as calcium salt, magnesium salt and the like, and basicsalts such as organic base salts such as ammonium salt, trimethylaminesalt, triethylamine salt, pyridine salt, picoline salt,dicyclohexylamine salt, N,N-dibenzylethylenediamine salt and the like.Although the reaction is usually carried out in the conventional solventsuch as water, alcohols such as methanol, ethanol and the like, acetone,dioxane, acetonitrile, chloroform, methylene chloride, ethylenechloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide andpyridine, the reaction may be carried out in any other organic solventsas long as they have no adverse effect on the reaction. Theseconventional solvents may be used as a mixture with water.

When Compound (II-11) is used as the form of a free acid or a saltthereof in this reaction, it is desirable that the reaction is carriedout in the presence of the normally used condensing agent such asso-called Vilsmeier regent and the like prepared by a reaction ofN,N′-dicyclohexylcarbodiimide;N-cyclohexyl-N′-morpholinoethylcarbodiimide;N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide;N,N′-diethylcarbodiimide, N,N′-diisopropylcarbodiimide,N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide;N,N′-carbonylbis(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; polyethyl phosphate;polyisopropyl phosphate; phosphorus oxychloride;diphenylphosphorylazide; thionyl chloride; oxalyl chloride; lower alkylhaloformate such as ethyl chloroformate; isopropyl chloroformate and thelike; triphenylphosphine; 2-ethyl-7-hydroxybenzisooxazolium salt,2-ethyl-5-(m-sulfophenyl)isooxazoliumhydroxide internal salt;N-hydroxybenzotriazole;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole;N—N′-dimethylformamide with thionyl chloride, phosgene, trichloromethylchloroformate, phosphorus oxychloride or the like. Alternatively, thereaction may be carried out in the presence of an inorganic base or anorganic base such as alkali metal bicarbonate salt,tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine and the like. A reaction temperature isnot particularly limited, but the reaction is carried out under coolingor under warming.

An amount of Compound (XVI) to be used is 1 to 10 mole equivalent,preferably 1 to 3 equivalent relative to Compound (II-11).

A reaction temperature is usually −30° C. to 100° C.

A reaction time is usually 0.5 to 20 hours.

In addition, when a mixed acid anhydride is used, Compound (II-11) andchlorocarbonic ester (e.g. methyl chlorocarbonate, ethylchlorocarbonate, isobutyl chlorocarbonate etc.) are reacted in thepresence of a base (e.g. triethylamine, N-methylmorpholine,N,N-dimethylaniline, sodium bicarbonate, sodium carbonate, potassiumcarbonate etc.) and is further reacted with Compound (XVI).

An amount of Compound (XVI) to be used is usually 1 to 10 moleequivalent, preferably 1 to 3 mole equivalent relative to Compound(II-11).

A reaction temperature is usually −30° C. to 100° C.

A reaction time is usually 0.5 to 20 hours.

The thus obtained Compound (II-12) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under the reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

When X¹ is C—COOR¹⁶ in Compound (III), the conversion can be carried outas follows:

wherein the symbols are as defined above.

Step L and step M can be carried out according to step L in the scheme 8and step M in the scheme 9, respectively, to prepare Compound (III-4)and Compound (III-5).

wherein R¹⁹ is an optionally substituted alkyl group, allyl group,hydroxy group, amino group or sulfanyl group, and the other symbols areas defined above.

In the present method, Compound (II-13) is prepared by a reactionbetween Compound (V) and a nucleophilic regent.

Examples of the nucleophilic regent include metal phenolate, metalalcoholate, Grignard regent, alkyl metal regent, aryl metal regent andthioalcoholate.

An amount of the nucleophilic regent to be used is preferably about 1 toabout 5 mole equivalent relative to Compound (V).

Examples of a solvent having no adverse effect on the reaction include:ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatichydrocarbons such as benzene, toluene and xylene; amides such asN,N-dimethylformamide and 1-methylpyrrolidone; sulfoxides such asdimethyl sulfoxide. These solvents may be used by mixing at anappropriate ratio.

A reaction temperature is usually about −50° C. to about 150° C.,preferably about −10 to about 100° C.

A reaction time is usually about 0.5 to about 20 hours.

The thus obtained Compound (II-13) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under the reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

wherein the symbols are as defined above.

Step N can be carried out according to step N in the scheme 11 toprepare Compound (III-4).

wherein A-6 is the same as A, and the other symbols are as definedabove.

In step H, an amino group of Compound (IV-5) is converted into adiazonium salt, and ylide is reacted thereon to prepare Compound(VIII-3). Diazotization in this method is carried out in the presence ofan acid in a solvent having no adverse effect on the reaction accordingto the conventional method. As the acid, for example, acetic acid andhydrochloric acid are used. As the diazotizing agent, sodium nitrite,alkyl nitrite or sulfated nitrosyl is used.

As the solvent, water, dioxane, tetrahydrofuran and the like are used.

A reaction temperature is usually about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

A reaction time is about 0.5 to about 20 hours.

The thus obtained diazonium salt of Compound (IV-5) is reacted withylide produced from Compound (XVII) to prepare Compound (VIII-3). Thepresent step is carried out in the presence of a base in a solventhaving no adverse effect on the reaction. Examples of the base include:alkali metal salts such as potassium carbonate; amines such as pyridine,triethylamine, N,N-dimethylaniline and1,8-diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassiumhydride and sodium hydride; and alkali metal alkoxides such as sodiummethoxide, sodium ethoxide and potassium t-butoxide.

An amount of these bases to be used is preferably about 1 to about 3mole equivalent relative to Compound (XVII).

Examples of the solvent having no adverse effect on the reaction includearomatic hydrocarbons such as benzene, toluene and xylene; ethers suchas tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbonssuch as chloroform and dichloromethane; amides such asN,N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. Thesesolvents may be used by mixing at an appropriate ratio.

Since the thus obtained Compound (VIII-3) is unstable depending on akind of the compound, it is used in the next step without isolation andpurification.

Step I, step J and step K can be carried out according to step I, step Jand step K, respectively, to prepare Compound (II-14) and Compound(II-15).

When R³ is a hydrogen atom in Compound (II) the following conversion ispossible.

wherein the symbols are as above.

In step O, Compound (II-4) is subjected to alkylation, acylation,carbamoylation, oxycarbonization or thiocarbamoylation to prepareCompound (II-6).

The reaction is carried out according to the conventional method. Inalkylation, alkyl halide is reacted, in acylation, acid halide or acidanhydride is reacted, in carbamoylation, isocyanate or carbonylimidazoleis reacted and, thereafter, amine is reacted, in oxycarbonization,oxycarbonyl halide or oxycarboic acid anhydride is reacted and, inthiocarbamoylation, thioisocyanate is reacted, respectively, to preparethe compound. The present reaction is generally carried out in thepresence of a base in a solvent having no adverse effect on thereaction. Examples of the base include alkali metal salts such aspotassium hydroxide, sodium hydroxide, sodium bicarbonate and potassiumcarbonate; amines such as pyridine, triethylamine, N,N-dimethylanilineand 1,8-diazabicyclo[5,4,0]undec-7-ene; metal hydrides such as potassiumhydride and sodium hydride; and alkali metal alkoxides such as sodiummethoxide, sodium ethoxide and potassium t-butoxide.

An amount of these bases to be used is preferably about 1 to about 5mole equivalent relative to Compound (II-4).

Examples of the solvent having no adverse effect on the reactioninclude: aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as tetrahydrofuran, dioxane and diethyl ether: halogenatedhydrocarbons such as chloroform and dichloromethane; amides such asN,N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. Thesesolvents may be used by mixing at an appropriate ratio.

A reaction temperature is usually about −50° C. to about 150° C.,preferably about −10° C. to about 120° C.

A reaction time is usually about 0.5 to about 20 hours.

The thus obtained Compound (II-6) can be isolated and purified by theknown isolating and purifying methods, for example, concentration,concentration under the reduced pressure, extraction with solvent,crystallization, recrystallization, transfer dissolution andchromatography.

When R³ is a hydrogen atom in Compound (III), the following conversionis possible.

wherein the symbols are as above.

Step O, step J and step K can be carried out according to step O in thescheme 14, respectively, to prepare Compound (III).

All the compounds used or obtained in the present invention includecorresponding salts, even if specifically stated, and they can beexchanged to one another by a per se known method or modified methodsthereof.

When the compounds or salts thereof obtained by the present inventionare asymmetric molecules, they can be separated into d-form isomer andl-form isomer according to conventional optical resolution methods.

The compound or its salt obtained by the present invention may be usedin a next step as its reaction mixture without sufficient purification.

Compound (I), (II), (III) or (IIIa) of the present invention has anexcellent Ca receptor modulating activity and enhances the secretion ofPTH, and therefore useful as drugs for treating bone diseases,kidney-acting drugs, central nervous system and endocrine-acting drugs,digestive system-acting drugs, and the like. Further, the toxicity islow. Therefore, Compound (I), (II), (III) or (IIIa) may be safelyadministered to mammalian animals (for example, human, rat, mouse, dog,rabbit, cat, cow, horse, pig, and the like).

Thus, a pharmaceutical composition containing compound (I), (II), (III)or (IIIa) of the present invention is expected to be useful in thetreatment and prevention of diseases, in which Ca receptor modulatingactivity is required, such as

Ca receptor modulating drugs: primary or secondary hyper parathyroidism;hypoparathyroidism; hyperthyroidism; hypothyroidism; Graves' disease;Hashimoto's toxicosis; Paget's disease; hypercalcemia associated withmalignant tumor; hypercalcemia; hypocalcemia; postmenopausalosteoporosis; senile osteoporosis; secondary osteoporosis; osteomalacia;renal osteodystrophy; fracture; osteoarthritis; rheumatoid arthritis;osteosarcoma; myeloma; hypertension; diabetes; myocardial infarction;Hachington's diseases; Parkinson's diseases; Alzheimer's disease;dementia; cerebral apoplexy; brain tumor; spinal injury; diabetic renaldisease; renal insufficiency; gastric ulcer; duodenal ulcer; Basedow'sdisease; parathyroid gland tumor; thyroid gland tumor; arteriosclerosis;and the like;Ca receptor antagonistic drugs: hyperthyroidism; hypocalcemia;postmenopausal osteoporosis; senile osteoporosis; secondaryosteoporosis; osteomalacia; renal osteodystrophy; fracture;osteoarthritis; rheumatoid arthritis; osteosarcoma; myeloma; centralnervous system diseases; and the like, in particular osteoporosis.

The dosage of Compound (I), (II), (III) or (IIIa) can be selected invarious ways depending on the administration route and the symptom of apatient to be treated. The dosage as Compound (I), (II), (III) or (IIIa)per an adult (a body weight of 50 kg) can be usually selected in a rangeof about 0.1 mg to about 500 mg, preferably about 1 mg to about 100 mgin the case of oral administration and in a range of about 0.01 mg toabout 100 mg, further preferably about 0.1 mg to about 10 mg in the caseof parenteral administration. The dosage can be administered with beingdivided in 1-3 times daily.

Compound (I), (II), (III) or (IIIa) of the present invention can beformulated with a pharmaceutically acceptable carrier and can be orallyor parenterally administered as solid formulations such as tablets,capsules, granules, powders, or the like; or liquid formulations such assyrups, injections, or the like. Also, there can be preparedformulations for transdermal administration such as patchings,cataplasms, ointments (including creams), plasters, tapes, lotions,liquids and solutions, suspensions, emulsions, sprays, and the like.

As for a pharmaceutically acceptable carrier, a variety of organic orinorganic carrier substances, which have been conventionally employed asformulation materials, is used and compounded as a bulking agent, alubricant, a binding agent, and a disintegrator in solid formulations; avehicle, a solubilizing agent, a suspending agent, an isotonicity agent,a buffering agent, and an analgesic in liquid formulations. Ifnecessary, formulation excipients such as a preservative, anantioxidant, a stabilizer, a coloring agent, a sweetening agent, and thelike can be used.

Preferred examples of the bulking agent include lactose, sucrose,D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid,and the like. Preferred examples of the lubricant include magnesiumstearate, potassium stearate, talc, colloidal silica, and the like.Preferred examples of the binding agent include crystalline cellulose,α-starch, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, and the like.Preferred examples of the disintegrator include starch, carboxymethylcellulose, calcium carboxymethyl cellulose, croscarmellose sodium,sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose,and the like. Preferred examples of the vehicle include water forinjection, alcohol, propylene glycol, macrogol, sesame oil, corn oil,and the like.

If necessary, for the purpose of taste masking, enteric coating, orprolonged action, oral formulations can be prepared by coating by a perse known method. Examples of this coating agent includehydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose,hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68[polyoxyethylene (160) polyoxypropylene (30) glycol], cellulose acetatephthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethylcellulose acetate phthalate, Eudragit (manufactured by Rohm Company,methacrylic acid-acrylic acid copolymer), and the like.

Preferred examples of the solubilizing agent include polyethyleneglycol, propylene glycol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate, and thelike. Preferred examples of the suspending agent include surface activeagents such as stearyltriethanolamine, sodium lauryl sulfate,laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniumchloride, glycerin monostearate, and the like; hydrophilic, highmolecular substances such as polyvinyl alcohol, polyvinyl pyrrolidone,sodium carboxymethyl cellulose, methyl cellulose, hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and thelike; and so on. Preferred examples of the isotonicity agent includesodium chloride, glycerin, D-mannitol, and the like. Preferred examplesof the buffering agent include buffer solutions of a phosphate, anacetate, a carbonate, a citrate, or the like. Preferable examples of theanalgesic include benzyl alcohol and the like. Preferred examples of thepreservative include paraoxybenzoic acid esters, chlorobutanol, benzylalcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and thelike. Preferred examples of the antioxidant include sulfites, ascorbicacid, and the like.

The following examples, preparations and experiments describe the mannerand process of making and using the present invention and areillustrative rather than limiting. It is to be understood that there maybe other embodiments which fall within the spirit and scope of thepresent invention as defined by the claims appended hereto.

Abbreviations employed herein are defined below.

DCM=dichloromethaneDCE=dichloroethaneDMAP=dimethylaminopyridineDMF=dimethylformamideWSC=1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochlorideM+H=monoisotopic mass plus one protonMe=methylEt=ethylPh=phenylh=hoursmin=minutesHPLC=high performance liquid chromatographyHOBt=hydroxybenzotriazoleLC/MS=liquid chromatography/mass spectrometryMS=mass spectrometryRt=retention timeTEA=triethylamineTFA=trifluoroacetic acidIPE=diisopropyletherTLC=thin layer chromatographyTHF=tetrahydrofuranTMSCN=trimethylsilyl cyanideHATU=O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafulorophosphateDIPEA=diisopropylethylamine

Example 1 Ethyl5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate

Step A: A mixture of 4,4,4-trifluoro-1-phenyl-1,3-butanedione 1 (6.97 g,32.24 mmol) and ethyl 3-aminopyrazole-4-carboxylate 2 (5.0 g, 32.22mmol) in AcOH (100 mL) was refluxed for 4 h. The mixture was cooled toroom temperature and concentrated and precipitated crystals werecollected by filtration to give 8.63 g (79%) of the title compound asyellow crystals. ¹H NMR (CDCl₃, 200 MHz): 1.47 (3H, t, J=7.0 Hz), 4.47(2H, q, J=7.0 Hz), 7.54-7.61 (3H, m), 7.80 (1H, s), 8.23-8.28 (2H, m),8.68 (1H, s).

Step B: To a solution of 3 (3.51 g, 10.3 mmol) in MeOH was added NaBH₄(1.4 g, 3.7 mmol) at room temperature. The whole was stirred at the sametemperature for 5 h, quenched with saturated citric acid solution,concentrated in vacuo, and extracted with AcOEt. The extract wassuccessively washed with aq. NaHCO₃, water and brine, dried over MgSO₄and then concentrated to give 1.73 g (49%) of compound 4 as colorlessoil. ¹H HMR (CDCl₃, 200 MHz): 1.32 (3H, t, J=6.8 Hz), 2.28-2.46 (1H, m),2.50-2.61 (1H, m), 4.25 (2H, q, J=6.8 Hz), 4.58 (1H, dd, J=11.4, 3.4Hz), 4.85 (1H, ddd, J=3.4, 3.0, 2.6 Hz), 6.15 (1H, s) 7.34-7.48 (5H, m),7.74 (1H, s).

Compounds of Examples 2-14, shown in the Table 1, were prepared in amanner similar to that described in Example 1.

TABLE 1 Physiological Example Structure Name Data 2

ethyl 5-(2-naphthyl)-7- (trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate mp 120-122° C. 3

ethyl 5-(4-methoxyphenyl)- 7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate mp 105-109° C. 4

ethyl 5-(4-chlorophenyl)-7- (trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate IR (KBr) 3376, 2984,1680, 1597, 1578, 1541 cm⁻¹ 5

ethyl 5-(3-pyridinyl)-7- (trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 341(M + H)⁺ 6

ethyl 7-benzyl-5-phenyl- 4,5,6,7-tetrahydro- pyrazolo[1,5-a]pyrimidine-3-carboxylate MS (ESI, m/z) 362 (M + H)⁺ 7

ethyl 7-methyl-5-phenyl- 4,5,6,7-tetrahydro- pyrazolo[1,5-a]pyrimidine-3-carboxylate MS (ESI, m/z) 286 (M + H)⁺ 8

ethyl (5-(4-ethylphenyl)-7- (trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 368(M + H)⁺ 9

ethyl 5-(2-methoxyphenyl)- 7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate ¹H NMR (CDCl₃, 200MHz): 1.33 (3H, t, J = 7.2 Hz), 2.16-2.34 (1H, m), 2.34- 2.61 (1H, m)3.88 (3H, s), 4.26 (2H, q, J = 7.2 Hz), 4.80-4.91 (1H, m), 5.00 (1H, dd,J = 11.4, 2.6 Hz), 6.08 (1H, s), 6.92-7.08 (2H, m), 7.30-7.39 (1H, m),7.50-7.55 (1H, m), 7.74 (1H, s) 10

ethyl 5-(3-methoxyphenyl)- 7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate ¹H NMR (CDCl₃, 200MHz): 1.32 (3H, t, J = 7.0 Hz), 2.27-2.45 (1H, m), 2.51- 2.61 (1H, m),3.84 (3H, s), 4.25 (2H, q, J = 7.0 Hz), 4.55 (1H, dd, J = 11.4, 2.8 Hz),4.76-4.93 (1H, m) 5.76- 4.93 (1H, m), 6.15 (1H, s), 6.89-7.03 (3H, m),7.30- 7.38 (1H, m), 7.74 (1H, s). 11

ethyl 5-(2-chlorophenyl)-7- (trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate ¹H NMR (CDCl₃, 200MHz): 1.34 (3H, t, J = 7.2 Hz), 2.14-2.32 (1H, m), 2.66- 2.78 (1H, m),4.27 (2H, q, J = 7.0 Hz), 4.81-4.97 (1H, m), 5.07 (1H, dd, J = 11.4, 3.0Hz), 6.11 (1H, s), 7.28-7.46 (3H, m), 7.66-7.70 (1H, m), 7.75 (1H, s).12

ethyl 5-(3-chlorophenyl)-7- (trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate ¹H NMR (CDCl₃, 200MHz): 1.37 (3H, t, J = 7.0 Hz), 2.26-2.44 (1H, m), 2.50- 2.61 (1H, m),4.26 (2H, q, J = 7.0 Hz), 4.57 (1H, dd, J = 11.6, 3.0 Hz), 4.76-4.93(1H, m), 6.16 (1H, s), 7.29-7.46 (4H, m), 7.74 (1H, s). 13

ethyl 2-methyl-7- (trifluoromethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate mp 142-143° C. 14

ethyl 5-(2-furyl)-7- (trifluoromethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate mp 86° C.

Example 15 Ethyl7,7-dimethyl-5-(2-pyridyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate

Step A: To a stirred solution of compound 1 (7.0 g, 44.3 mmol) in THF(100 mL) was added n-BuLi (1.6 M hexane solution, 28 mL, 44.8 mmol) at−78° C. After the mixture was stirred for 30 min, compound 2 (6.34 g,44.3 mmol) was added thereto. The resulting mixture was stirred at−78-−50° C. for 2 h, quenched with saturated citric acid solution andextracted with AcOEt. The extract was successively washed with water andbrine, dried over MgSO₄ and then concentrated in vacuo. The residue waschromatographed on silica gel with AcOEt/hexane (1:9) as an eluent togive 3.16 g (44% yield) of compound 3 as colorless liquid.

Step B: To a solution of compound 3 and compound 4 in methoxyethanol (60mL) was added TFA (4.47 g, 39.2 mmol) with ice-water cooling. Themixture was refluxed for 12 h, diluted with AcOEt, and the mixture waswashed with saturated NaHCO₃ solution, water and brine, dried overMgSO₄, and then concentrated in vacuo. The residue was chromatographedon silica gel with AcOEt/hexane (1:4) as an eluent to give 2.03 g (36%yield) of compound 5 as colorless prisms.

Step C: A mixture of 5 (1.98 g, 6.96 mmol) and 10% Pd—C (1.0 g) in EtOH(100 mL) was stirred for 2 h under the H₂ atmosphere (balloon pressure).After the insoluble materials were filtered off, the residue wasconcentrated in vacuo to give the residue. Crystallization fromhexane/IPE gave the title compound 6 (1.00 g, 48%) as colorless solid.¹H NMR (CDCl3, 200 MHz): 1.34 (3H, t, J=7.0 Hz), 4.26 (2H, q, J=7.0 Hz),4.80 (1H, dd, J=11.4, 2.6 Hz), 6.39 (1H, s), 7.24-7.31 (1H, m), 7.51(1H, d, J=7.6 Hz), 7.76 (1H, td, J=7.6, 1.8 Hz), 8.60-8.63 (1H, m).

Compounds of Examples 16-29, 439-447 and 924-938 shown in the Table 2,were prepared in a manner similar to that described in Example 15.

TABLE 2 Physiological Example Structure Name Data 16

ethyl 7,7-dimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS (ESI, m/z) 300 (M + H)⁺ 17

ethyl 5′-phenyl-5′,6′-dihydro- 4′H-spiro[cyclopentane-1,7′-pyrazolo[1,5-a]pyrimidine]- 3′-carboxylate MS (ESI, m/z) 326 (M + H)⁺ 18

ethyl 7,7-diethyl-5-phenyl- 4,5,6,7-tetrahydro- pyrazolo[1,5-a]pyrimidine-3-carboxylate MS (ESI, m/z) 300 (M + H)⁺ 19

ethyl 5′-phenyl-5′,6′-dihydro- 4′H-spiro[cyclohexane-1,7′-pyrazolo[1,5-a]pyrimidine]- 3′-carboxylate MS (ESI, m/z) 328 (M + H)⁺ 20

ethyl 5-phenyl-4,5,5a,6,7,8,9,9a- octahydropyrazolo[1,5-a]quinazoline-3-carboxylate MS (ESI, m/z) 326 (M + H)⁺ 439

ethyl 5-(2-methoxyphenyl)- 7,7-dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS (ESI, m/z) 330 (M + H)⁺ 440

ethyl 2-ethyl-7,7-dimethyl 5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS (ESI, m/z) 328 (M + H)⁺ 441

ethyl 2,7,7-trimethyl-5-(2- methylphenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 328(M + H)⁺ 442

ethyl 7,7-dimethyl-5-(2- pyridinyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS (ESI, m/z) 301 (M + H)⁺ 443

ethyl 7,7-dimethyl-5-(5- methyl-1,3-thiazol-2-yl)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidine-3- carboxylate MS (ESI,m/z) 321 (M + H)⁺ 444

ethyl 5-(3-methoxyphenyl)- 7,7-dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS (ESI, m/z) 330 (M + H)⁺ 445

ethyl 2,7,7-trimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS (ESI, m/z) 314 (M + H)⁺ 446

ethyl 5-(2-fluorophenyl)- 2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 332(M + H)⁺ 447

methyl 7,7-dimethyl-2- (methylthio)-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 332(M + H)⁺ 924

ethyl 5-(2-fluorophenyl)-7,7- dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS (ESI, m/z) 318 (M + H)⁺ 925

ethyl 5-(2-chlorophenyl)-7,7- dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS (ESI, m/z) 334 (M + H)⁺ 926

ethyl 7,7-dimethyl-5-(2- methylphenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS (ESI, m/z) 314 (M + H)⁺ 927

ethyl 5-(4-methoxyphenyl)- 7,7-dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS (ESI, m/z) 330 (M + H)⁺ 928

ethyl 5-(2-chlorophenyl)- 2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 348(M + H)⁺ 929

ethyl 5-(2-methoxyphenyl)- 2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 344(M + H)⁺ 930

ethyl 5-(3-fluorophenyl)- 2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 332(M + H)⁺ 931

ethyl 2,7,7-trimethyl-5-(3- methylphenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 328(M + H)⁺ 932

ethyl 5-(3-methoxyphenyl)- 2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 344(M + H)⁺ 933

ethyl 5-(4-fluorophenyl)- 2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 332(M + H)⁺ 934

ethyl 2,7,7-trimethyl-5-(4- methylphenyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 328(M + H)⁺ 935

ethyl 5-(4-methoxyphenyl)- 2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 344(M + H)⁺ 936

ethyl 2,7,7-trimethyl-5-(2- thienyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS (ESI, m/z) 320 (M + H)⁺ 937

ethyl 5-(2,4-dimethylphenyl)- 7,7-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 328(M + H)⁺ 938

ethyl 2-(2-hydroxyethoxy)- 7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI, m/z) 360(M + H)⁺

Example 215-Phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylicAcid

A mixture of 1, 1.5 N KOH solution (14 mL) and EtOH (20 mL) was stirredat 60° C. for 12 h, acidified with saturated citric acid solution, andthe precipitated solid was collected by filtration, which was washedwith water and IPE to give 1.59 g (76% yield) of the title compound ascolorless prisms. mp 184.8-185.0° C., ¹H NMR (CDCl3, 300 MHz): 2.31-2.44(1H, m), 2.50-2.59 (1H, m), 4.59 (1H, dd, J=11.4, 3.0 Hz), 4.79 (1H, m),6.10 (1H, s), 7.20-7.26 (5H, m), 7.78 (1H, s).

Compounds of Examples 22-39, 448-458 and 939-953 shown in the Table 3,were prepared in a manner similar to that described in Example 21.

TABLE 3 Physiological Example Structure Name Data 22

5-(2-naphthyl)-7- (trifluoromethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 143-145° C. 23

5-(3-pyridinyl)-7- (trifluoromethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid MS (ESI, m/z) 315 (M + H)⁺ 24

7-benzyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid MS (ESI, m/z) 336 (M + H)⁺ 25

5-(4-methoxyphenyl)-7- (trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylic acid mp 154-155° C. 26

5-(4-chlorophenyl)-7- (trifluoromethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 186-187° C. 27

7-methyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 165-167° C. 28

5-(4-ethylphenyl)-7- (trifluoromethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 165-168° C. 29

5-(2-furyl)-7-(trifluoromethyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 156-157° C. 30

5-(2-methoxyphenyl)-7- (trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylic acid mp 189-190° C. 31

5-(3-methoxyphenyl)-7- (trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylic acid mp 169-170° C. 32

5-(2-chlorophenyl)-7- (trifluoromethyl)-4,5,6,7,-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylic acid mp 177-179° C. 33

5-(3-chlorophenyl)-7- (trifluoromethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 194-195° C. 34

2-methyl-7-(trifluoromethyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 165-166° C. 35

7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 201-202° C. 36

5′-phenyl-5′,6′-dihydro-4′H- spiro[cyclopentane-1,7′-pyrazolo[1,5-a]pyrimidine]- 3′-carboxylic acid MS (ESI, m/z) 298 (M +H)⁺ 37

7,7-diethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 158-160° C. 39

5′-phenyl-5′,6′-dihydro-4′H- spiro[cyclohexane-1,7′-pyrazolo[1,5-a]pyrimidine]- 3′-carboxylic acid mp 155° C. 39

5-phenyl-4,5,5a,6,7,8,9,9a- octahydropyrazolo[1,5-a]quinazoline-3-carboxylic acid mp 158-160° C. 448

5-(2-methoxyphenyl)-7,7- dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid MS (ESI, m/z) 302 (M + H)⁺ 449

2-ethyl-7,7-dimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid MS (ESI, m/z) 300 (M + H)⁺ 450

4-benzyl-7,7-dimethyl-5- phenyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrimi- dine-3-carboxylic acid MS (ESI, m/z) 362 (M + H)⁺451

2,7,7-trimethyl-5-(2- methylphenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid MS (ESI, m/z) 300 (M + H)⁺ 452

7,7-dimethyl-5-(2-pyridinyl)- 4,5,6,7-tetrahydro- pyrazolo[1,5-a]pyrimi-dine-3-carboxylic acid MS (ESI, m/z) 273 (M + H)⁺ 453

7,7-dimethyl-5-(5-methyl- 1,3-thiazol-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylic acid MS (ESI, m/z) 293(M + H)⁺ 454

5-(3-methoxyphenyl)-7,7- dimethyl-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyri- midine-3-carboxylic acid MS (ESI, m/z) 302(M + H)⁺ 455

2,7,7-trimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3- carboxylic acid MS (ESI, m/z) 286 (M + H)⁺ 456

4,7,7-trimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3- carboxylic acid MS (ESI, m/z) 286 (M + H)⁺ 457

5-(2-fluorophenyl)-2,7,7- trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid MS (ESI, m/z) 304 (M + H)⁺ 458

7,7-dimethyl-2-(methylthio)- 5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acd MS (ESI, m/z) 318 (M + H)⁺ 939

5-(2-fluorophenyl)-7,7- dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 167-168° C. 940

5-(2-chlorophenyl)-7,7- dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 167-168° C. 941

7,7-dimethyl-5-(2- methylphenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid ¹H NMR (CDCl₃, 300 MHz) δ 1.59 (3H, s),1.64 (3H, s), 1.92- 2.17 (2H, m), 2.38 (3H, s), 4.89 (1H, dd, J = 10.8,3.9 Hz), 5.92 (1H, s), 7.16-7.29 (3H, m), 7.53 (1H, dd, J = 7.2, 1.8Hz), 7.69 (1H, s). 942

5-(4-methoxyphenyl)-7,7- dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 196-197° C. 943

5-(2-chlorophenyl)-2,7,7- trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 173-174° C. 944

5-(2-methoxyphenyl)-2,7,7- trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 198-199° C. 945

5-(3-fluorophenyl)-2,7,7- trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 153-155° C. 946

2,7,7-trimethyl-5-(3- methylphenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 146-148° C. 947

5-(3-methoxyphenyl)-2,7,7- trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 151-152° C. 948

5-(4-fluorophenyl)-2,7,7- trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 173-174° C. 949

2,7,7-trimethyl-5-(4- methylphenyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 181-182° C. 950

5-(4-methoxyphenyl)-2,7,7- trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 178-179° C. 951

2,7,7-trimethyl-5-(2- thienyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 186-187° C. 952

5-(2,4-dimethylphenyl)-7,7- dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 155-157° C. 953

2-(2-hydroxyethoxy)-7,7- dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylic acid mp 137-139° C.

Example 40N-Cyclooctyl-5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Cyclooctylamine (24 mg, 0.19 mmol) was added to a suspension of compound1 (0.05 g, 0.16 mmol), WSC (37 mg, 0.19 mmol), HOBt (29 mg, 0.19 mmol)and DMAP (23 mg, 0.19 mmol) in DMF (1.5 mL). The reaction mixture wasstirred at room temperature for 14 h, diluted with DCM (0.5 mL) andsaturated NaHCO₃ solution (0.5 mL), and then separated using PHASE-SEPfiltration syringe. The organic layer was concentrated and loaded ontopreparative HPLC (Gilson 215 system). The purest fractions were combinedto give 64.6 mg (96% yield) of the title compound as a white solid.Reverse Phase LC/MS: CAPCELLPAKCC18UG120, S-3 μm, 2.0×50 mm, UVdetection at 220, 8 min. gradient 10-100% Solvent B/A (Solvent A: CH₃CNwith 0.1% TFA, Solvent B: H₂O with 0.1% TFA), 0.5 mL/min. Rt=1.90 min,(96% pure). MS (M+H: 421).

Example 41N-(1-ethyl-1-(4-(trifluoromethyl)phenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 3 (0.5 g, 1.84 mmol) and HATU (0.84 g, 2.21 mmol) inDMF (3 mL) was added DIPEA (0.67 mL, 3.68 mmol) at room temperature.After 30 min, compound 2 (0.59 g, 2.21 mmol) was added thereto. Theresulting mixture was stirred at 80° C. for 18 h, concentrated in vacuo,and the residue was chromatographed on silica gel with AcOEt/hexane(1/1) as an eluent to give 0.28 g (31% yield) of compound 4 as colorlessprisms. mp 193-194° C.

Compounds of Examples 42-434, 459-867 and 954-1008 shown in the table 4,were prepared in a manner similar to that described in Example 40 or 41.

Lengthy table referenced here US20090215746A1-20090827-T00001 Pleaserefer to the end of the specification for access instructions.

Example 1009 Ethyl7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate

Racemic compound obtained in Example 16 (80 g) was subjected topreparative high performance liquid chromatography (HPLC) to affordoptically pure materials (38 g, 99.8% ee (shorter retention time) and 39g, 99.4% ee (longer retention time)). [column: CHIRALCEL OD 50 mmφ×500mm (manufactured by Daicel Kagaku Kogyo Kabushiki Kaisha), temperature:30° C., mobile phase: hexane/Ethanol=95/5, flow rate: 60 ml/minute,detection wavelength: 254 nm, and 1 shot: about 800 mg].

Compounds of Examples 1010-1017 shown in the Table 8˜11, were preparedin a manner similar to that described in Example 1009.

TABLE 8 Physiological Example Structure Name Data 1010

ethyl 2,7,7-trimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS(ESI, m/z) 314 (M + H)+, shorter retentiontime 1011

ethyl 2,7,7-trimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS(ESI, m/z) 314 (M + H)+, longer retentiontime

The determination of the optical purity was carried out by HPLC using achiral column (column: CHIRALCEL OD 4.6 mmφ×250 mm (manufactured byDaicel Kagaku Kogyo Kabushiki Kaisha), temperature: about 30° C., mobilephase: hexane/ethanol=96/4, flow rate: 0.5 ml/minute, and detectionwavelength: 254 nm).

TABLE 9 1012

ethyl 5-(2-fluorophenyl)-7,7- dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS(ESI, m/z) 318 (M + H)+, shorter retentiontime 1013

ethyl 5-(2-fluorophenyl)-7,7- dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate MS(ESI, m/z) 318 (M + H)+, longer retentiontime

The determination of the optical purity was carried out by HPLC using achiral column (column: CHIRALPAK AD 4.6 mmφ×250 mm (manufactured byDaicel Kagaku Kogyo Kabushiki Kaisha), temperature: about 30° C., mobilephase: hexane/IPA=95/5, flow rate: 0.5 ml/minute, and detectionwavelength: 254 nm).

TABLE 10 1014

ethyl 5-(2-fluorophenyl)-2,7, 7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS(ESI, m/z) 332 (M +H)+, shorter retention time 1015

ethyl 5-(2-fluorophenyl)-2,7, 7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS(ESI, m/z) 332 (M +H)+, longer retention time

The determination of the optical purity was carried out by HPLC using achiral column (column: CHIRALPAK AD 4.6 mmφ×250 mm (manufactured byDaicel Kagaku Kogyo Kabushiki Kaisha), temperature: about 30° C., mobilephase: hexane/ethanol=995/5, flow rate: 0.5 ml/minute, and detectionwavelength: 220 nm).

TABLE 11 1016

ethyl 5-(2-chlorophenyl)-2,7, 7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS(ESI, m/z) 348 (M +H)+, shorter retention time 1017

ethyl 5-(2-chlorophenyl)-2,7, 7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS(ESI, m/z) 348 (M +H)+, longer retention time

The determination of the optical purity was carried out by HPLC using achiral column (column: CHIRALCEL OD 4.6 mmφ×250 mm (manufactured byDaicel Kagaku Kogyo Kabushiki Kaisha), temperature: about 30° C., mobilephase: hexane/ethanol=95/5, flow rate: 0.5 ml/minute, and detectionwavelength: 258 nm).

Example 1018(−)-7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylicAcid

A mixture of 1 (0.73 g) obtained in Example 1009, KOH (0.41 g), H₂O (20ml) and EtOH (20 mL) was stirred at 90° C. for 12 h, acidified with 1NHCl, and extracted with AcOEt. The extract was washed with brine, driedover MgSO₄, and concentrated in vacuo to give 0.55 g (83% yield) of thetitle compound as colorless prisms ([α]_(D) ^(20° C.)=−85.33, in CHCl₃,C=0.46). mp 205-206° C., ¹H NMR (CDCl3, 300 MHz): 1.59 (3H, s), 1.66(3H, s), 2.05-2.15 (2H, m), 4.64 (1H, dd, J=9.6, 5.4 Hz), 6.04 (1H, s),7.30-7.41 (5H, m), 7.73 (1H, s).

Compounds of Examples 1019-1027 shown in the Table 12, were prepared ina manner similar to that described in Example 1018.

TABLE 12 Physiological Example Structure Name Data 1019

(+)-7,7-dimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 205-206° C. [α]_(D) ^(20°C.) = 86.01,in CHCl₃, C = 0.48. 1020

(+)-2,7,7-trimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 190-192° C. [α]_(D) ^(21°C.) = 103.65,in CHCl₃, C = 1.17. 1021

(−)-2,7,7-trimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 190-192° C. [α]_(D) ^(21°C.) =−109.21, in CHCl₃, C = 1.25. 1022

(+)-5-(2-fluorophenyl)-7,7- dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 169-170° C. [α]_(D) ^(20°C.) = 107.91,in CHCl₃, C = 0.48. 1023

(−)-5-(2-fluorophenyl)-7,7- dimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 165-166° C. [α]_(D) ^(20°C.) =−108.59, in CHCl₃, C = 0.47. 1024

(+)-5-(2-fluorophenyl)-2,7, 7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 150-151° C. [α]_(D) ^(21°C.) = 123.34,in CHCl₃, C = 0.33. 1025

(−)-5-(2-fluorophenyl)-2,7, 7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 150-151° C. [α]_(D) ^(21°C.) =−122.39, in CHCl₃, C = 0.47. 1026

(+)-5-(2-chlorophenyl)-2,7, 7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 163-164° C. [α]_(D) ^(21°C.) = 177.21,in CHCl₃, C = 0.28. 1027

(−)-5-(2-chlorophenyl)-2,7, 7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid mp 163-164° C. [α]_(D) ^(21°C.) =−166.12, in CHCl₃, C = 0.25.

Example 1028(S)—N-(1-(4-Chlorophenyl)-1-ethylpropyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamideHydrochloride

Step A: To a solution of 1 (0.4 g, 1.47 mmol) and HATU (0.67 g, 1.77mmol) in DMF (5 mL) was added DIPEA (0.57 g, 4.41 mmol) at roomtemperature. After 1 h, compound 2 (0.41 g, 1.77 mmol) was addedthereto. The resulting mixture was stirred at 80° C. for 12 h, andconcentrated in vacuo. The residue was diluted with AcOEt, washed withsat.NaHCO₃aq and brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was chromatographed on silica gel with AcOEt/hexane (1/1) togive 0.41 g (62% yield) of compound 4 as colorless prisms. mp 105-106°C. [α]_(D) ^(20° C.)=−17.68 in CHCl₃, C=0.30.

Step B: To a stirred solution of compound 3 (90 mg, 0.2 mmol) in Et₂O (3mL) was added 4M HCl-AcOEt (0.1 mL, 0.4 mmol) at room temperature. Theprecipitate was collected by filtration to give 60 mg (62% yield) ofcompound 4 as prisms. mp 130-132° C. [α]_(D) ^(20° C.)=24.3 in CHCl₃C=0.48.

Compounds of Examples 1029-1122 shown in the Table 13, were prepared ina manner similar to that described in Example 1028.

TABLE 13 Ex- Physiological ample Structure Name Data 1029

(5S)-N-1-adamantyl-7,7- dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp 226-227° C.,[α]_(D) ^(20°C.) = −37.40 in CHCl₃, C = 0.24. 1030

(5R)-N-1-adamantyl-7,7- dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp 226-227° C.[α]_(D) ^(20°C.) = 37.0 in CHCl₃, C = 0.24. 1031

(5S)-N-(1-ethyl-1-(4- (trifluoromethyl)phenyl) propyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp165-166° C. [α]_(D) ^(20°C.) = −15.10 in CHCl₃, C = 0.25. 1032

(5R)-N-(1-ethyl-1-(4- (trifluoromethyl)phenyl) propyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp165-166° C. [α]_(D) ^(20°C.) = 14.4 in CHCl₃, C = 0.25. 1033

(5R)-N-(1-(4-chlorophenyl)- 1-ethylpropyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp105-106° C. [α]_(D) ^(20°C.) = 17.92 in CHCl₃, C = 0.28. 1034

(5S)-N-(1-ethyl-1-(4- methylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 139-140° C. [α]_(D) ^(20°C.) = −19.67 inCHCl₃, C = 0.34 1035

(5S)-N-(1-ethyl-1-(4- methylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 142-143° C., [α]_(D) ^(21°C.) = 31.05 inCHCl₃, C = 0.65. HCl salt 1036

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 139-140° C. [α]_(D) ^(22°C.) = 16.33 inCHCl₃, C = 0.60. 1037

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 150-151° C., [α]_(D) ^(21°C.) = −27.99 inCHCl₃, C = 0.80. HCl salt 1038

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 140-141° C. [α]_(D) ^(22°C.) = −14.02 inCHCl₃, C = 0.30. PhSO₃H salt 1039

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 151-152° C. [α]_(D) ^(21°C.) = −14.42 inCHCl₃, C = 0.33. p-TsOH salt 1040

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 140-141° C. [α]_(D) ^(21°C.) = −9.10 inCHCl₃, C = 0.40. 0.5 H₂SO₄ salt 1041

(5S)-N-(1-(4-chlorophenyl)- 1-ethylpropyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 131-132° C. [α]_(D) ^(20°C.) = −22.63 inCHCl₃, C = 0.22. 1042

(5R)-N-(1-(4-chlorophenyl)- 1-ethylpropyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 128-129° C. [α]_(D) ^(20°C.) = 22.24 inCHCl₃, C = 0.23. 1043

(5R)-N-(1-(4-chlorophenyl)- 1-ethylpropyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 193-194° C. [α]_(D) ^(21°C.) = −7.85 inCHCl₃, C = 0.30. HCl salt 1044

(5S)-N-(1-ethyl-1-(4- methylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 78-80° C. [α]_(D) ^(20°C.) = −23.5 inCHCl₃, C = 0.51. 1045

(5S)-N-(1-ethyl-1-(4- methylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 194-195° C. [α]_(D) ^(20°C.) = 9.3 inCHCl₃, C = 0.48. HCl salt 1046

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 78-80° C. [α]_(D) ^(20°C.) = 25.3 inCHCl₃, C = 0.50. 1047

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 206-207° C. [α]_(D) ^(25°C.) = −8.1 inCHCl₃, C = 0.52. HCl salt 1048

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 188-189° C. [α]_(D) ^(20°C.) = −4.4 inCHCl₃, C = 0.44. CH₃SO₃H salt 1049

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 161-162° C. [α]_(D) ^(20°C.) = −9.5 inCHCl₃, C = 0.50. PhSO₃H salt 1050

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 120-122° C. [α]_(D) ^(20°C.) = −8.8 inCHCl₃, C = 0.51. p-TsOH salt 1051

(5R)-N-(1-ethyl-1-(4- ethylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 149-150° C., [α]_(D) ^(21°C.) = −16.76 inCHCl₃, C = 0.39. HCl salt 1052

(5R)-N-(1-(4-tert- butylphenyl)-1-ethylpropyl)- 7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp 139-140°C., [α]_(D) ^(21°C.,) = −13.94 in CHCl₃, C = 0.36. HCl salt 1053

(5R)-N-(1-ethyl-1- phenylpropyl)-7,7-dimethyl- 5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp 129-130° C.,[α]_(D) ^(21°C.) = −24.66 in CHCl₃, C = 0.38. HCl salt 1054

(5R)-N-(1-ethyl-1- phenylpropyl)-2,7,7- trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp 185-186° C.,[α]_(D) ^(21°C.) = −10.56 in CHCl₃, C = 0.39. HCl salt 1055

(5R)-N-(1,1-diethylbutyl)- 2,7,7-trimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp 176-177° C.,[α]_(D) ^(21°C.) = −1.98 in CHCl₃, C = 0.35. HCl salt 1056

(5R)-N-(1-ethyl-1-(4- ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide MS(ESI, m/z) 459 (M + H)+, [α]_(D) ^(20°C.) =25.0 in CHCl₃, C = 0.53. 1057

(5R)-N-(1-ethyl-1-(4- ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 163-164° C., [α]_(D) ^(21°C.) = −7.96 inCHCl₃, C = 0.46. HCl salt 1058

(5R)-N-(1-ethyl-1-(4- ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 160-161° C., [α]_(D) ^(20°C.) = −2.9 inCHCl₃, C = 0.56. CH₃SO₃H salt 1059

(5R)-N-(1-ethyl-1-(4- ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 165-166° C., [α]_(D) ^(20°C.) = −7.4 inCHCl₃, C = 0.49. PhSO₃H salt 1060

(5R)-N-(1-ethyl-1-(4- ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 160-161° C., [α]_(D) ^(20°C.) = −8.1 inCHCl₃, C = 0.49. P-TsOH salt 1061

(5R)-N-(1-ethyl-1-(5-methyl- 1-phenyl-1H-pyrazol-3-yl)propyl)-2,7,7-trimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide MS(ESI, m/z) 511 (M + H)+ 1062

(5R)-N-(1-ethyl-1-(5-methyl- 1-phenyl-1H-pyrazol-3-yl)propyl)-2,7,7-trimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 194-195° C. 2 HCl salt 1063

(5R)-N-(1-ethyl-1-(2- fluorophenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 180-182° C., [α]_(D) ^(21°C.) = −8.60 inCHCl₃, C = 0.62. HCl salt 1064

(5R)-N-(1-ethyl-1-(4- hydroxyphenyl)propyl)- 2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp 160-161°C., [α]_(D) ^(21°C.) = 15.41 in CHCl₃, C = 0.36. 1065

(5S)-N-(1-ethyl-1- phenylpropyl)- 2,7,7-trimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp 182-183° C.,[α]_(D) ^(21°C.) = 11.36 in CHCl₃, C = 0.36. HCl salt 1066

(5R)-N-(1-(5-chloro-2- thienyl)-1-ethylpropyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide MS(ESI, m/z) 471 (M + H)+ 1067

(5R)-N-(1-ethyl-1-(4- (methylthio)phenyl)propyl)- 7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp 151-152°C., 1068

(5R)-N-(1-(4-chloro-3- methylphenyl)-1- ethylpropyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp150-151° C. HCl salt 1069

(5R)-N-(1-(3-chloro-4- methylphenyl)-1- ethylpropyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp129-130° C. HCl salt 1070

(5R)-N-(1-(1-benzothien-2- yl)-1-ethylpropyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 127-128° C. HCl salt 1071

(5R)-N-(1-(4- (dimethylamino)phenyl)-1- ethylpropyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp141-142° C. 2 HCl salt 1072

(5R)-N-(1,1-diethylbutyl)- 7,7-dimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp 185-186° C., HClsalt 1073

(5R)-N-(1-ethyl-1-(4- iodophenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 179-180° C., HCl salt 1074

(5R)-ethyl 4-(1-ethyl-1- (((2,7,7-trimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidin-3- yl)carbonyl)amino)propyl)benzoate mp 125-126° C., HCl salt 1075

(5R)-N-(1-ethyl-1-(4- (hydroxymethyl)phenyl)propyl)-2,7.7-trimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 168-169° C. HCl salt 1076

(5R)-4-(1-ethyl-1-(((-2,7,7- trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidin-3- yl)carbonyl)amino)propyl) benzoicacid mp 234-236° C. 1077

(5R)-N-(1-ethyl-1-(4- (hydroxymethyl)phenyl) propyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp159-160° C., HCl salt 1078

(+)-N-[1-ethyl-1-(4- methylphenyl)propyl]-5-(2-fluorophenyl)-7,7-dimethyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 139-140° C., [α]_(D) ^(20°C.) = +9.66 inCHCl₃, C = 0.47. HCl salt 1079

(+)-N-[1-ethyl-1-(4- methylphenyl)propyl]-5-(2-fluorophenyl)-7,7-dimethyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide mp 161-163° C. [α]_(D) ^(20°C.) = 39.5 inCHCl₃, C = 0.50. 1080

mp 135-136° C., [α]_(D) ^(20°C.) = −11.19 in CHCl₃, C = 0.49. HCl saltof Example 1079 1081

mp 144-146° C. [α]_(D) ^(20°C.) = −5.1 in CHCl₃, C = 0.50. p-TsOH saltof Example 1079 1082

mp 147-149° C. [α]_(D) ^(20°C.) = −4.1 in CHCl₃, C = 0.49. PhSO₃H saltof Example 1079 1083

(5S)-N-(1-ethyl-1-(4- methylphenyl)propyl)-5-(2- fluorophenyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp203-204° C. [α]_(D) ^(21°C.) = −1.29 in CHCl₃, C = 0.54. HCl salt 1084

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-5-(2- fluorophenyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamideMS(ESI, m/z) 463 (M + H)+ 1085

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-5-(2- fluorophenyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp156-158° C. [α]_(D) ^(20°C.) = 1.29 in CHCl₃, C = 0.52. HCl salt 1086

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-5-(2- fluorophenyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp180-181° C. [α]_(D) ^(20°C.) = 4.9 in CHCl₃, C = 0.52. CH₃SO₃H salt 1087

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-5-(2- fluorophenyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp172-174° C. [α]_(D) ^(20°C.) = 0.4 in CHCl₃, C = 0.48. p-TsOH salt 1088

(5R)-N-(1-ethyl-1-(4- methylphenyl)propyl)-5-(2- fluorophenyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp170-171° C. [α]_(D) ^(20°C.) = 0.1 in CHCl₃, C = 0.49. PhSO₃H salt 1089

(5R)-N-(1-ethyl-1-(4- ethylphenyl)propyl)-5-(2- fluorophenyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp138-139° C. [α]_(D) ^(20°C.) = 2.6 in CHCl₃, C = 0.57. HCl salt 1090

(5S)-5-(2-chlorophenyl)-N- (1-ethyl-1-(4- methylphenyl)propyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp173-174° C. [α]_(D) ^(20°C.) = −48.2 in CHCl₃, C = 0.50. HCl salt 1091

(5R)-5-(2-chlorophenyl)-N- (1-ethyl-1-(4- methylphenyl)propyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp136-137° C. [α]_(D) ^(20°C.) = 66.9 in CHCl₃, C = 0.50. 1092

(5R)-5-(2-chlorophenyl)-N- (1-ethyl-1-(4- methylphenyl)propyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp176-177° C. [α]_(D) ^(20°C.) = 48.0 in CHCl₃, C = 0.57. HCl salt 1093

(5R)-5-(2-chlorophenyl)-N- (1-ethyl-1-(4- methylphenyl)propyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp171-172° C. [α]_(D) ^(20°C.) = 42.4 in CHCl₃, C = 0.62. CH₃SO₃H salt1094

(5R)-5-(2-chlorophenyl)-N- (1-ethyl-1-(4- methylphenyl)propyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp150-151° C. [α]_(D) ^(20°C.) = 37.8 in CHCl₃, C = 0.51. P-TsOH salt 1095

N-(1-ethyl-1-(4- isopropylphenyl)propyl)- 2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide mp 134-136°C. HCl salt 1096

(5R)-3-(((4R)-4-(benzyloxy)- 2,2-diethyl-1-pyrrolidinyl)carbonyl)-2,7,7- trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine MS(ESI, m/z) 501 (M + H)+ HCl salt1097

(3R)-5,5-diethyl-1-(((5R)- 2,7,7-trimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidin-3-yl)carbonyl)-3- pyrrolidinol mp162-164° C. 1098

(3R)-5,5-diethyl-1-(((5R)- 2,7,7-trimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidin-3-yl)carbonyl)-3- pyrrolidinol mp140-142° C. HCl salt 1099

(5R)-3-(((4R)-2,2-diethyl-4- methoxy-1- pyrrolidinyl)carbonyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine mp132-134° C. 1100

(5R)-3-(((4R)-2,2-diethyl-4- methoxy-1- pyrrolidinyl)carbonyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine HClsalt EA Calcd. For C₂₅H₃₇N₄O₂Cl•H₂O: C. 62.68; H. 8.21; N. 11.70. FoundC. 62.89; H. 8.43; N. 11.50. 1101

(5R)-3-((2,2-diethyl-4-fluoro- 1-pyrrolidinyl)carbonyl)-2,7,7-trimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidineMS(ESI, m/z) 413 (M + H)+ 1102

(5R)-3-((2,2-diethyl-4-fluoro- 1-pyrrolidinyl)carbonyl)-2,7,7-trimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidineHCl salt EA Calcd. For C₂₄H₃₄N₄OClF•0.9 H₂O: C. 61.96; H. 7.76; N.12.04. Found C. 62.26; H. 8.01; N. 11.83 1103

(5R)-3-(((4R)-4-(benzyloxy)- 2,2-diethyl-1- pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine mp118-120° C. 1104

(5R)-3-(((4R)-4-(benzyloxy)- 2,2-diethyl-1- pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine HCl saltEA Calcd. For C₃₀H₃₉N₄O₂Cl•H₂O: C. 66.59; H. 7.64; N. 10.35. Found. C.66.83; H. 7.73; N. 10.05 1105

(5S)-3-(((4R)-4-(benzyloxy)- 2,2-diethyl-1- pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine mp172-174° C. 1106

(5S)-3-(((4R)-4-(benzyloxy)- 2,2-diethyl-1- pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine HCl salt¹H-NMR (CDCl₃) δ: 0.82 (6 H, dt, J = 36.3, 7.2 Hz), 1.58-1.72 (1 H, m),1.93 (6 H, d, J = 54.3 Hz), 2.00-2.26 (7 H, m), 3.67 (1 H, dd, J = 12.3,2.7 Hz), 3.79 (1 H, dd, J = 9.9, 5.4 Hz), 4.15- 4.24 (1 H, m), 4.56 (2H, dd, J = 39.3, 12.0 Hz), 4.64 (1 H, dd, J = 10.2, 4.8 Hz), 7.30-7.46(10 H, m), 7.88 (1 H, bs). 1107

(5R)-3-(((4S)-4-(benzyloxy)- 2,2-diethyl-1- pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine mp173-175° C. 1108

(5R)-3-(((4S)-4-(benzyloxy)- 2,2-diethyl-1- pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine HCl salt¹H-NMR (CDCl₃) δ: 0.83 (6 H, dt, J = 30.9, 7.5 Hz), 1.60-1.78 (1 H, m),1.68 (6 H, d, J = 24.3 Hz), 1.96-2.24 (7 H, m), 3.70-3.78 (1 H, m),3.88-4.00 (1 H, m), 4.14-4.24 (1 H, m), 4.54 (2 H, dd, J = 25.2, 11.7Hz), 4.61 (1 H, dd, J = 9.6, 3.9 Hz), 7.28- 7.44 (10 H, m), 7.59 (1 H,bs). 1109

(5S)-3-(((4S)-4-(benzyloxy)- 2,2-diethyl-1- pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine mp116-118° C. 1110

(5S)-3-(((4S)-4-(benzyloxy)- 2,2-diethyl-1- pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine HCl salt¹H-NMR (CDCl₃) δ: 0.84 (6 H, dt, J = 14.4, 9.2 Hz), 1.68-2.24 (8 H, m),1.86 (6 H, d, J = 43.5 Hz), 3.50-3.60 (1 H, m), 3.76-3.92 (1 H, m),4.14-4.27 (1 H, m), 4.57 (2 H, dd, J = 33.9, 12.0 Hz), 4.58-4.68 (1 H,m), 7.30-7.46 (10 H, m), 7.79 (1 H, bs). 1111

(5R)-3-(((4R)-2,2-diethyl-4- methoxy-1- pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine mp148-150° C. 1112

(5R)-3-(((4R)-2,2-diethyl-4- methoxy-1- pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine mp148-150° C. HCl salt 1113

(5R)-3-(((4S)-2,2-diethyl-4- methoxy-1- pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine mp122-124° C. 1114

(5R)-3-(((4S)-2,2-diethyl-4- methoxy-1- pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine mp122-124° C. HCl salt 1115

(3R)-1-(((5R)-7,7-dimethyl- 5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)carbonyl)- 5,5-diethyl-3-pyrroldinol mp 250-252° C.1116

(3R)-1-(((5R)-7,7-dimethyl- 5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)carbonyl)- 5,5-diethyl-3-pyrroldinol mp 250-252° C. HClsalt 1117

(3S)-1-(((5R)-7,7-dimethyl- 5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)carbonyl)- 5,5-diethyl-3-pyrroldinol mp 249-251° C.1118

(3S)-1-(((5R)-7,7-dimethyl- 5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)carbonyl)- 5,5-diethyl-3-pyrroldinol mp 247-249° C. HClsalt 1119

(5R)-3-((2,2-diethyl-4-fluoro- 1-pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine mp210-212° C. more polar 1120

mp 209-211° C. HCl salt of Example 1119 1121

(5R)-3-((2,2-diethyl-4-fluoro- 1-pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine mp216-218° C. less polar 1122

mp 216-218° C. HCl salt of Example 1121

Example 435N-(1-adamantyl)-7-ethyl-5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: To a stirred solution of compound 1 (2.00 g, 6.00 mmol) in DCM(50 mL) was added triethylaluminium (2.0 M hexane solution, 18 mL, 36mmol) at room temperature. After the mixture was stirred for 2 h, it wasquenched with water, and extracted with AcOEt. The extract wassuccessively washed with water and brine, dried over MgSO₄ and thenconcentrated in vacuo to give compound 2 (2.20 g, 100% yield) as yellowsyrup. MS (ESI, m/z) 366 (M+H)⁺.

Step B: A mixture of compound 2 (2.20 g, 6.00 mmol), LiOH (0.51 g, 12.15mmol), EtOH (50 mL) and H₂O (30 mL) was stirred at 70° C. for 12 h,concentrated in vacuo, diluted with aq.citric acid solution andextracted with AcOEt. The extract was successively washed with water,saturated NaHCO₃ solution and brine, dried over MgSO₄ and thenconcentrated to give compound 3 (2.00 g, 100%) as colorless crystals. MS(ESI, m/z) 352 (M+H)⁺.

Step C: 1-Adamantylamine (0.72 g, 4.76 mmol) was added to a suspensionof compound 3 (1.60 g, 4.74 mmol), WSC (0.91 g, 4.74 mmol), HOBt (0.64g, 4.74 mmol) and DMAP (0.58 g, 4.75 mmol) in DMF (20 mL). The reactionmixture was stirred at 70° C. for 13 h and then concentrated in vacuo.The residue was chromatographed on silica gel with AcOEt/hexane (1/6) asan eluent to give compound 4 (0.71 g, 32%) as colorless crystals. MS(ESI, m/z) 472 (M+H)⁺.

Step D: To a solution of 4 (0.58 g, 1.23 mmol) in EtOH was added NaBH₄(0.2 g, 5.29 mmol) at room temperature. The whole was stirred at 60° C.for 3 h, concentrated in vacuo, diluted with water and extracted withAcOEt. The extract was successively washed with aq. NaHCO₃, water andbrine, dried over MgSO₄ and then concentrated to give 0.43 g (74%) ofcompound 5 as colorless crystals. MS (ESI, m/z) 474 (M+H)⁺.

Compounds of Examples 436, shown in the Table 5, were prepared in amanner similar to that described in Example 435.

TABLE 5 Example Structure Name Physical Data 436

N-(1-adamantyl)-7-methyl-5- phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide MS (ESI, m/z)462 (M + H)⁺

Example 4372-cyclohexyl-4-methyl-N-(1-methyl-1-phenylethyl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine-8-carboxamide

Step A: To a 250 mL round bottom flask equipped with magnetic stir barand 2 addition funnels was added 1.0 g (6.44 mmol) of compound 1 by 3.5ml of conc. hydrochloric acid and 7.0 ml of water. The solution wascooled to 0° C. and a solution containing 0.50 g (7.25 mmol) of sodiumnitrite in 2 ml of water dropwise. After complete addition, the reactionwas allowed to stir for 30 min. at 0° C., followed by the addition of 65ml of dichloromethane and 35 ml of a saturated sodium bicarbonatesolution while maintaining the reaction temperature below 10° C. Asolution containing 2.05 g (6.44 mmol) of1-triphenylphosphoroanylidene-2-propanone in 30 ml of dichloromethanewas then added dropwise. After complete addition, the reaction wasallowed to stir for 5 min., diluted with 50 ml of dichloromethane andwashed with water. The organic phase was separate and the solventremoved under reduced pressure to afford 3.50 g (100%) of crude compound2 which is taken on without further purification. MS Calcd.: 206; Found207 (M+H).

Step B: To a solution containing the crude product from above in 30 mlof ethanol and 30 ml of THF under a nitrogen atmosphere was added 1.20 g(3.72 mmol) of sodium borohydride. The reaction was allowed to stir atroom temperature for 30 min. The reaction was diluted with ethyl acetateand washed with water. The organic phase was dried over MgSO₄.Filtration, removal of solvent and purification of the residue viaBiotage chromatography eluting with 70% AcOEt/hexanes gave 0.79 g(58.9%) of compound 3 as a pale yellow solid. MS Calcd.: 208; Found 209(M+H)

Step C: A solution containing 0.54 g (2.59 mmol) of compound 3 and 0.18g of LiOH (7.52 mmol) in 15 ml of ethanol and 10 ml of water was heatedto 70° C. After 1.5 h, HPLC of reaction mixture indicated no startingmaterial remaining. The ethanol was removed under reduced pressure andthe residue acidified with 1N hydrochloric acid and extracted with ethylacetate. The organic phase was dried over magnesium sulfate. Filtrationand removal of solvent gave 0.48 g (92.2%) of compound 4. MS Calcd.:180; Found 181 (M+H).

Step D: To a solution containing 2.80 g (15.54 mmol) of compound 4 in150 ml of DMF under a nitrogen atmosphere was added 6.50 g (17.10 mmol)of HATU, 2.31 g (17.10 mmol) of cumyl amine and 2.98 ml (17.10 mmol) ofdiisopropylethylamine. The reaction was heated to 50° C. overnight,diluted with ethyl acetate and washed with water. The organic phase wasdried over magnesium sulfate. Filtration, removal of solvent andpurification of the residue via Biotage chromatography eluting with 60%AcOEt/hexanes gave 3.09 g (66.9%) of compound 5. MS Calcd.: 297; Found298 (M+H).

Step E: To a Parr flask was added 1.11 g (3.90 mmol) of compound 5 and75 ml of EtOH. The flask was purged with nitrogen and 0.30 g of platinumoxide added. The flask was evacuated and pressurized to 20 psig hydrogen(3×) then pressurized to 50 psig hydrogen and shaken for 1 h. Aftercompletion as determined by HPLC, the reaction was filtered through GF/Ffilter paper and the filtrate concentrated under reduced pressure toafford 1.1 g (100%) of compound 6. MS Calcd.: 299; Found 300 (M+H)

Step F: To a solution containing 0.43 g (1.44 mmol) of compound 6 in 40ml of DCE under a nitrogen atmosphere was added 0.30 ml (2.89 mmol) ofcyclohexanone followed by 0.90 g (4.25 mmol) of sodium triacetoxyborohydride. The reaction was allowed to stir at room temperatureovernight. The reaction was diluted with dichloromethane and washed withsaturated sodium bicarbonate solution. The organic phase was dried overMgSO₄. Filtration, removal of solvent and purification of the residuevia Biotage chromatography eluting with 75% AcOEt/hexanes gave 0.35 g(63.7%) of compound 7. MS Calcd.: 381; Found 382 (M+H)

Example 4384-Methyl-N-(1-methyl-1-phenylethyl)-2-phenyl-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine-8-carboxamide

To a solution containing 0.20 g (0.71 mmol) of compound 1 in 25 ml ofDCM under a nitrogen atmosphere at −78° C. was added 0.36 g (0.64 mmol)of triphenylbismuth diacetate followed by 0.02 g (0.075 mmole) of copper(II) dipivalate. The reaction was allowed to warm to 0° C. over 1.5 h.The reaction was diluted with dichloromethane and washed with saturatesodium bicarbonate. The organic phase was dried over magnesium sulfate.Filtration, removal of solvent and purification of the residue viaBiotage chromatography eluting with 70% AcOEt/hexanes gave 0.025 g(9.4%) of compound 2. MS Calcd.: 375; Found 376 (M+H)

Example 11231-(7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-methyl-2-(4-methylphenyl)-1-propanone

Step A

4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2): To a 100 mL round bottom flask equipped with a magnetic stirbar was added 1.80 g (6.01 mmol) of7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrimidine-3-carboxylicacid ethyl ester, 30 mL of DMF and 0.786 mL (6.61 mmol) of benzylbromide, followed by 0.265 g (6.6 mmol) of sodium hydride (60%dispersion in mineral oil) which was added in several portions. After 2h, the reaction was quenched with water and the product was extractedwith AcOEt. The combined organic layers were washed with brine, driedover sodium sulfate, filtered and concentrated to give the crudeN-benzylated ester as a golden colored oil. The crude ester wasdissolved in 15 mL of ethanol and 2.5 mL of 6 N potassium hydroxide wasadded. The solution was then heated to 70° C. for 18 h at which time nostarting material could be detected by HPLC analysis. The crude reactionmixture was concentrated in vacuo and diluted with water. The aqueoussolution was acidified with 6 N HCl and the resulting cream-coloredprecipitate was collected by filtration. The crude acid thus isolatedwas dissolved in AcOEt, dried over sodium sulfate, filtered andconcentrated to a cream colored powder. The resulting acid was washedwith several portions of hexanes and dried in vacuo to give 1.95 g (90%)of the title compound as an off white powder. ¹H NMR (DMSO-d₆) δ 1.10(s, 3H), 1.40 (s, 3H), 1.98-2.16 (m, 2H), 3.71 (d, J=15.4 Hz, 1H), 4.36(dd, J=4.5, 11.5 Hz, 1H), 5.81 (d, J=15.6 Hz), 6.97 (dd, J=1.4, 7.2 Hz,2H), 7.26-7.45 (m, 7H), 7.67 (s, 1H), 11.81 (s, 1H). MS Calcd. 361;Found: 344 (M−OH).

Step B

4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylicacid methoxy-methyl-amide (3): To a 5 mL NMP solution containing 0.72 g(1.99 mmol) of 2 was added 0.91 g (2.39 mmol) ofO-7-azabenzotriazolo-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HATU) and 0.416 mL (2.39 mmol) of diisopropylethylamine. After stirringfor 30 min, 0.233 g (2.39 mmol) of O,N-dimethyl-hydroxylaminehydrochloride was added and the reaction heated to 50° C. After 1 h, thereaction mixture was poured into water and extracted with AcOEt. Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo to give a crude oil.Purification of this oil by flash chromatography eluting with a 60 to50% hexanes/AcOEt gradient gave 0.65 g (81%) of the title compound as alight golden colored solid. ¹H NMR (CDCl₃) δ 1.37 (s, 3H), 1.56 (s, 3H),2.06-2.16 (m, 2H), 3.25 (s, 3H), 3.49 (s, 3H), 3.90 (d, J=16.0 Hz, 1H),4.45 (dd, J=5.1, 11.3 Hz, 1H), 5.06 (d, J=16.2 Hz, 1H), 6.98 (dd, J=1.8,6.1 Hz, 2H), 7.20-7.24 (m, 3H), 7.30-7.34 (m, 1H), 7.37-7.41 (m, 4H),7.74 (s, 1H). MS Calcd.: 404; Found: 405 (M+H).

Step C

1-(4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-(4-methylphenyl)ethanone(4): To 0.65 g (1.61 mmol) of 3 dissolved in 20 mL of THF was added 6.4mL (3.2 mmol) of a 0.5 M solution of 4-methylbenzylmagnesium chloride inTHF via syringe over 10 min. After stirring at room temperature for 1 h,the reaction was quenched by addition of approximately 2 mL of saturatedaqueous ammonium chloride. The reaction was then diluted with AcOEt anddried over sodium sulfate. Filtering the solution through a short plugof silica gel and concentrating in vacuo provided the crude product asan oil. Purification of this oil by flash chromatography eluting with75% hexanes/AcOEt gave 0.64 g (89%) of the title compound as a whitefoam. MS Calcd.: 449; Found: 450 (M+H).

Step D

1-(4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-(4-methylphenyl)-1-propanone(5): To 0.64 g (1.42 mmol) of 4 dissolved in 10 mL of THF was added0.177 mL (2.85 mmol) of iodomethane followed by 0.11 g (2.8 mmol) ofsodium hydride (60% dispersion in mineral oil). After stirring at roomtemperature for 2 h, the reaction was quenched by addition ofapproximately 2 mL of saturated aqueous ammonium chloride. The reactionwas then diluted with AcOEt and dried over sodium sulfate. Filtering thesolution through a short plug of silica gel and concentrating in vacuoprovided the crude product. Purification by flash chromatography elutingwith 90% hexanes/ethyl acetate gave 0.42 g (64%) of the title compoundas a cream colored powder. MS Calcd.: 463; Found: 464 (M+H).

Step E

1-(4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-methyl-2-(4-methylphenyl)-1-propanone(6): To 0.110 mL (0.785 mmol) of diisopropyl amine dissolved in 5 mL ofTHF at −78° C. was added 0.314 mL (0.785 mmol) of a 2.5 M solution ofn-butyllithium in hexanes. After stirring for 30 min, 0.28 g (0.604mmol) of 5 was added as a solution in 1 mL of THF. The reaction wasstirred at room temperature for 1 h before 0.049 mL (0.79 mmol) ofiodomethane was added as a solution in 1 mL of THF. After 1 h thereaction was quenched by addition of approximately 0.5 mL of saturatedaqueous ammonium chloride, diluted with AcOEt and dried over sodiumsulfate. Filtering the solution through a short plug of silica gel andconcentrating in vacuo provided the crude product. Purification by flashchromatography eluting with 90% hexanes/AcOEt gave 0.067 g (23%) of thetitle compound as an off white solid. MS Calcd.: 477; Found: 478 (M+H).

Step F

1-(7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-methyl-2-(4-methylphenyl)-1-propanone(7): To 0.060 g (0.126 mmol) of 6 dissolved in 4 mL of 1:1 THF:ethanolwas added 0.080 g of 10% palladium on carbon. The reaction vessel wascapped with a rubber septum and charged with hydrogen via a balloon.After 1 h, the catalyst was removed via filtration and the filtrateconcentrated to a cream colored solid. Purification by flashchromatography eluting with 90% hexanes/ethyl acetate gave 0.041 g (84%)of the title compound as a white solid.

¹H NMR (CDCl₃) δ 1.49 (s, 3H), 1.54 (s, 9H), 2.04-2.11 (m, 2H), 2.32 (s,3H), 4.63 (dd, J=4.1, 10.7 Hz, 1H), 6.66 (s, 1H), 7.12-7.26 (m, 5H),7.31-7.44 (m, 5H). MS Calcd.: 387; Found: 388 (M+H).

Compounds of Examples 1124-1131 shown in the Table 14, were prepared ina manner similar to that described in Example 1123.

TABLE 14 1124

2-(1,1′-biphenyl-4-yl)-1-(7,7- dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidin-3-yl)ethanone MS (ESI, m/z) 422 (M +H)⁺ 1125

1-(4-benzyl-7,7-dimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2- phenylethanone MS (ESI, m/z) 436 (M + H)⁺ 1126

1-(4-benzyl-7,7-dimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-phenyl-1- propanone MS (ESI, m/z) 450 (M + H)⁺ 1127

1-(7,7-dimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-phenyl-1- propanone MS (ESI, m/z) 360 (M + H)⁺ 1128

(1-(7,7-dimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-methyl-2- phenyl-1-propanone MS (ESI, m/z) 374 (M +H)⁺ 1129

2-(4-chlorophenyl)-1-(7,7- dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidin-3-yl)-1- propanone MS (ESI, m/z) 395(M + H)⁺ 1130

2-(4-chlorophenyl)-1-(7,7- dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidin-3-yl)-2-methyl-1- propanone MS (ESI,m/z) 409 (M + H)⁺ 1131

1-(7,7-dimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-(4- methylphenyl)-1-propanone MS (ESI, m/z) 374 (M +H)⁺

Example 11327,7-Dimethyl-3-((1-methyl-1-(4-methylphenyl)ethyl)sulfonyl)-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine

Step A

p-Tolylmethanesulfonylacetonitrile (2): To a 10 mL ethanol solutioncontaining 4.1 g (30 mmol) of p-tolylmethanethiol at 0° C. was added 4.1mL (30 mmol) of triethylamine and 4.4 g (30 mmol) of sodium iodide.After allowing the reaction to stir at room temperature forapproximately 30 min, the reaction cooled to 0° C. and 1.9 mL (30 mmol)of chloroacetonitrile was added dropwise as a solution in 10 mL ofethanol. The reaction was allowed to reach room temperature overnightand was subsequently filtered and concentrated. The concentrate waspartitioned between water and ether and separated. The ether layer waswashed successively with 2 N sodium carbonate and brine and was thenconcentrated to an oil that solidified. The crude solid was thendissolved in 90 mL of glacial acetic acid, treated with 12.1 mL (107mmol) of 30% hydrogen peroxide and heated to 100° C. The reaction wascooled to room temperature after 3 h at which time a white solidprecipitated. The precipitate was collected via filtration, washed withglacial acetic acid and dried in vacuo to give 6.4 g (69%) of the titlecompound as a white solid. ¹H NMR (CDCl₃) δ 2.39 (s, 3H), 3.70 (s, 2H),4.48 (s, 2H), 7.32 (dd, J=7.3, 40.2 Hz, 4H).

Step B

3-Ethoxy-2-p-tolylmethanesulfonylacrylonitrile (3): To a solution of 4.4g (21 mmol) of 2 in 17.5 mL (105 mmol) of triethylorthoformate was added9.9 mL (105 mmol) of acetic anhydride. The resulting solution was heatedto reflux for 18 h before being concentrated to a solid.

Recrystallization from AcOEt-hexanes gave 5.0 g (90%) of the titlecompound as a white solid.

¹H NMR (CDCl₃) δ 1.29 (t, J=7.0 Hz, 3H), 2.36 (s, 3H), 4.19 (q, J=7.0Hz, 2H), 4.35 (s, 2H), 7.23 (dd, J=8.0, 19.9 Hz) 7.37 (s, 1H).

Step C

7,7-Dimethyl-3-(4-methylbenzyl)sulfonyl)-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine(4): A slurry of 1.9 g (7.2 mmol) of 3 in 25 mL of ethanol was treatedwith 0.38 mL (7.9 mmol) of hydrazine monohydrate and heated to refluxfor 3 h. The reaction was concentrated in vacuo to give crude4-p-tolylmethanesulfonyl-2H-pyrazol-3-ylamine as a tan solid. The crudepyrazole, 1.3 g (7.9 mmol) of 3-methyl-1-phenyl-but-2-en-1-one and 2.8mL (36 mmol) of trifluoroacetic acid was dissolved in 25 mL of2-methoxyethanol and heated to reflux for 3 days. The reaction was thencooled to room temperature, concentrated in vacuo and dissolved inAcOEt. This solution was washed successively with saturated sodiumbicarbonate, water and brine before being dried over sodium sulfate. Thesolution was filtered, concentrated in vacuo and the resulting crudematerial was purified by flash chromatography eluting with a 75 to 33%hexanes/AcOEt gradient to give 1.25 g (44%) of the title compound as apowder. ¹H NMR (CDCl₃) δ 1.67 (s, 6H), 2.13 (s, 3H), 4.26 (s, 2H), 4.81(d, J=2.0 Hz, 1H), 6.39 (s, 1H), 7.05 (dd, J=8.0, 18.5 Hz, 4H), 7.20(dd, J=3.7, 7.4 Hz, 2H), 7.36-7.39 (m, 3H), 7.52 (s, 1H) MS Calcd.: 393;Found: 394 (M+H).

Step D

7,7-Dimethyl-3-((4-methylbenzyl)sulfonyl)-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(5): To 0.500 g (1.27 mmol) of 4 dissolved in 8 mL of 1:1 THF:ethanolwas added 0.50 g of 10% palladium on carbon. The reaction vessel wascapped with a rubber septum and charged with hydrogen via a balloon.After 2 days at room temperature, the catalyst was removed viafiltration and the filtrate concentrated to a solid. Purification byflash chromatography eluting with a 75 to 33% hexanes/AcOEt gradientgave 0.385 g (77%) of the title compound as a white solid. ¹H NMR(CDCl₃) δ 1.49 (s, 3H), 1.59 (s, 3H), 1.83-1.97 (m, 2H), 2.37 (s, 3H),4.09-4.24 (m, 3H), 5.03 (s, 1H), 7.06-7.13 (m, 6H), 7.30-7.39 (m, 3H),7.45 (s, 1H). MS Calcd.: 395; Found: 396 (M+H).

Step E

4-Benzyl-7,7-dimethyl-3-((4-methylbenzyl)sulfonyl)-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(6): To a solution of 0.34 g (0.86 mmol) of 5 in 10 mL of THF at 0° C.was added 0.128 mL (1.07 mmol) of benzyl bromide followed by 0.034 g(0.86 mmol) of sodium hydride (60% dispersion in mineral oil). Thereaction was allowed to warm to room temperature after 30 min andstirred for an additional 30 min before being quenched with water. Thequenched reaction was diluted with five volumes of water and extractedwith AcOEt. The combined organic layers were washed with brine, driedover sodium sulfate, filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography eluting with 70%hexanes/AcOEt to give 0.39 g (93%) of the title compound as a whitesolid. ¹H NMR (CDCl₃) δ 1.27 (s, 3H), 1.52 (s, 3H), 1.93-2.05 (m, 2H),2.27 (s, 3H), 3.83 (d, J=15.8 Hz, 1H), 4.18-4.30 (m, 3H), 5.51 (d,J=15.8 Hz, 1H), 6.98-7.00 (m, 2H), 7.09 (dd, J=8.2, 12.1 Hz, 4H), 7.17(d, J=6.8 Hz, 2H), 7.26-7.30 (m, 3H), 7.32-7.40 (m, 3H), 7.47 (s, 1H).

Step F

4-Benzyl-7,7-dimethyl-3-((1-(4-methylphenyl)ethyl)sulfonyl)-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(7): A solution of 0.23 g (0.47 mmol) of 6 in 4 mL of THF was cooled to0° C. and treated with 0.24 mL (0.59 mmol) of n-butyllithium (2.5 Msolution in hexanes) and allowed to reach room temperature for 20 min.After cooling the reaction to 0° C., 0.103 mL (1.66 mmol) of iodomethanewas added as a solution in 2 mL of THF. The reaction was allowed to warmto room temperature for 30 min at which time the reaction was quenchedwith a few drops of saturated ammonium chloride. The reaction was driedover sodium sulfate, filtered and concentrated in vacuo. The residue waspurified by flash chromatography eluting with 80% hexanes/AcOEt to give0.14 g (60%) of the title compound as a white solid. MS Calcd.: 499;Found: 500 (M+H).

Step G

4-Benzyl-7,7-dimethyl-3-((1-methyl-1-(4-methylphenyl)ethyl)sulfonyl)-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(8): Using the method described for the synthesis of 7, the titlecompound was prepared in 51% isolated yield. MS Calcd.: 513; Found: 514(M+H).

Step H

7,7-Dimethyl-3-((1-methyl-1-(4-methylphenyl)ethyl)sulfonyl)-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(9): To 0.075 g (0.146 mmol) of 8 dissolved in 6 mL of 1:1 THF:ethanolwas added 0.10 g of 10% palladium on carbon. The reaction vessel wascapped with a rubber septum and charged with hydrogen via a balloon.After 2 h at room temperature, the catalyst was removed via filtrationand the filtrate concentrated to give 0.056 g (91%) of the titlecompound as a white solid. MS Calcd.: 423; Found: 424 (M+H).

Compounds of Examples 1133-1134, shown in the Table 15, were prepared ina manner similar to that described in Example 1132.

TABLE 15 1133

3-((1-(4- chlorophenyl)ethyl)sulfonyl)- 7,7-dimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI, m/z) 431 (M + H)⁺ 1134

3-((1-(4-chlorophenyl)-1- methylethyl)sulfonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI,m/z) 445 (M + H)⁺

Example 11353-(3-Benzylpyrrolidine-1-sulfonyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine

Step A

(3-Benzylpyrrolidine-1-sulfonyl)acetonitrile (2): To a 20 mL ethersolution containing 1.34 g (8.31 mmol) of 3-benzylpyrrolidine cooled to−45° C. was added 0.61 g (4.4 mmol) of 2-cyanoethanesulfonyl chloride asa solution in 10 mL of ether. The reaction was allowed to warm to roomtemperature and was stirred for 24 h over which time an oil formed onthe flask wall. The ether solution was poured away from the oil andfiltered through a short plug of silica gel. The filtrate thus obtainedwas concentrated in vacuo to give a solid that was purified by flashchromatography eluting with 75% hexanes/AcOEt to give 1.25 g (44%) ofthe title compound as a wax.

¹H NMR (CDCl₃) δ 1.73-1.83 (m, 1H), 2.08-2.15 (m, 1H), 2.57-2.67 (m,1H), 2.71-2.79 (m, 2H), 3.21 (dd, J=8.2, 9.7, Hz, 1H), 3.49-3.55 (m,1H), 3.63 (dd, J=7.0, 9.4 Hz, 1H), 3.69-3.74 (m, 1H), 3.95 (s, 2H), 7.16(d, J=7.4 Hz, 2H), 7.21-7.33 (m, 3H).

Step B

2-(3-Benzylpyrrolidine-1-sulfonyl)-3-ethoxyacrylonitrile (3): To asolution of 0.14 g (0.53 mmol) of 2 in 0.43 mL (2.6 mmol) oftriethylorthoformate was added 0.25 mL (2.6 mmol) of acetic anhydride.The resulting solution was heated to reflux for 4 h before beingconcentrated to an oil. The crude oil thus obtained was purified byflash chromatography eluting with 75% hexanes/AcOEt to give 0.079 g(46%) of the title compound as a yellow oil. ¹H NMR (CDCl₃) δ 1.42 (t,J=7.2 Hz, 3H), 1.67-1.77 (m, 1H), 2.01-2.09 (m, 1H), 2.53-2.62 (m, 1H),2.71 (d, J=7.4 Hz, 2H), 3.05 (dd, J=8.4, 9.8 Hz, 1H), 3.35-3.41 (m, 1H),3.48 (dd, J=7.0, 9.5 Hz, 1H), 3.53-3.59 (m, 1H), 4.31 (q, J=7.2 Hz, 2H),7.15-7.17 (m, 2H), 7.19-7.23 (m, 1H), 7.26-7.31 (m, 2H), 7.76 (s, 1H).

Step C

3-(3-Benzylpyrrolidine-1-sulfonyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine(4): A 2 mL ethanol solution containing 0.079 g (0.247 mmol) of 3 wastreated with 0.013 mL (0.27 mmol) of hydrazine monohydrate and heated toreflux for 5 h. The reaction was concentrated in vacuo to give crude4-(3-benzylpyrrolidine-1-sulfonyl)-2H-pyrazol-3-ylamine. The crudepyrazole thus obtained was dissolved in 2 mL of 2-methoxyethanolcontaining 0.044 g (0.27 mmol) of 3-methyl-1-phenyl-but-2-en-1-one and0.038 mL (0.49 mmol) of trifluoroacetic acid was added. The mixture wasrefluxed for three days then concentrated and purified by flashchromatography eluting with 60% hexanes/AcOEt to give3-(3-benzylpyrrolidine-1-sulfonyl)-7,7-dimethyl-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidinethat was found to be only 90% pure by HPLC analysis. This material wasthen dissolved in 1 mL of 1:1 THF:ethanol and 0.010 g of 10% palladiumon carbon. The reaction vessel was capped with a rubber septum andcharged with hydrogen via a balloon. After 90 min at room temperature,the catalyst was removed via filtration and the filtrate concentrated toan oil. Purification by flash chromatography eluting with 75%hexanes/AcOEt gave 0.024 g (20% from 3) of the title compound as a lightyellow oil. ¹H NMR (CDCl₃) δ 1.55-1.66 (m, 7H), 1.94-2.03 (m, 1H),2.08-2.16 (m, 2H), 2.37-2.50 (m, 1H), 2.58-2.70 (m, 2H), 2.90-2.97 (m,1H), 3.18-3.27 (m, 1H), 3.31-3.42 (m, 2H), 4.53-4.60 (m, 1H), 5.71 (s,1H), 7.11-7.14 (m, 2H), 7.19-7.23 (m, 1H), 7.26-7.40 (m, 7H), 7.53 (s,1H). MS Calcd.: 450; Found: 451 (M+H).

Example 11364,4-Dimethyl-8-[5-(1-methyl-1-phenyl-ethyl)-[1,3,4]oxadiazol-2-yl]-2-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidine

Step A

2-Amino-1H-pyrrole-3-carboxylic acid ethyl ester (1):Carbamimidoyl-acetic acid ethyl ester (3.357 g, 25.8 mmol) was dissolvedin AcOEt (20 mL). Chloroacetaldehyde (50% solution in water, 1.8 mL,28.7 mmol) was added rapidly at room temperature. The solution stirredfor 2 minutes until a precipitant formed. The solution was then broughtto 65° C. for 0.5 h. The reaction mixture was then cooled and flashchromatographed with AcOEt. Product containing fractions wereconcentrated to give the desired material as a green solid. 0.68 gobtained, 31% yield. ¹H NMR (400 MHz, CDCl₃) δ 1.32 (t, J=7.2 Hz, 3H),4.24 (q, J=7.0 Hz, 2H), 5.08 (brs, 2H), 6.10-6.13 (m, 1H), 6.25 (t,J=3.12, 1 Hz), 8.60 (brs, 1H); MS Calcd.: 154; Found 155 (M+H).

Step B

4,4-Dimethyl-2-phenyl-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrimidine-8-carboxylicacid ethyl ester (2): Compound 1 (0.68 g, 4.41 mmol) was dissolved inDMF (5 mL). NaH (60% in mineral oil, 0.19 g, 4.7 mmol) was added at roomtemperature affording rapid gas evolution. The reaction stirred for 0.5h upon which 3-methyl-1-phenyl-but-2-en-1-one (0.50 g, 3.15 mmol) wasadded. The reaction stirred for 0.5 h upon which EtOH (5 mL) and NaBH₄(1.19 g) were added. The solution was brought to 60° C. for 0.5 h. andthen cooled to room temperature. The solution was quenched with water,extracted with Et₂O (3 times), dried (Na₂SO₄) and concentrated. Flashchromatography (10% AcOEt) to give the desired product as a tan solid(0.60 g, 63% yield). MS Calcd.: 298; Found 299 (M+H).

Step C

4,4-Dimethyl-2-phenyl-1,2,3,4-tetrahydro-pyrrolo[1,2,-a]pyrimidine-8-carboxylicacid hydrazide (3): Compound 2 (0.210 g, was diluted with anhydroushydrazine (5 mL) and heated to 100° C. for 3 days. The reaction was thencooled and diluted with water. The solution was extracted with AcOEt (3times), dried (Na₂SO₄) and concentrated. The residue was flashchromatographed (10% MeOH/AcOEt) to give the desired material. 0.12 g,60% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.54 (s, 6H), 1.99-2.13 (m, 2H),3.89 (brs, 2H), 4.64 (dd, J=3.5, 11.7 Hz, 1H), 6.02 (d, J=3.9 Hz), 6.22(d, J=3.9 Hz, 1H), 6.55 (brs, 1H), 6.74 (brs, 1H), 7.31-7.46 (m, 5H). MSCalcd.: 284; Found 285 (M+H).

Step D

4,4-Dimethyl-2-phenyl-1,2,3,4-tetrahydro-pyrrolo[1,2,-a]pyrimidine-8-carboxylicacid N-(2-methyl-2-phenyl-propionyl)-hydrazide (4):

Compound 3 (0.085 g, 0.30 mmol) was dissolved in THF (2 mL). HBTU (0.136g, 0.36 mmol), α,α-dimethyl-phenylacetic acid (0.059 g, 0.36 mmol), andDIEA (0.10 mL, 0.60 mmol) were added. The reaction stirred for 2 h. andwas concentrated. Flash chromatography (50% AcOEt/hexanes) gave thedesired product. 0.123 g obtained (96% yield). ¹H NMR (400 MHz, CDCl₃) δ1.49 (s, 3H), 1.50 (s, 3H), 1.60 (s, 3H), 1.61 (s, 3H), 1.95-2.10 (m,2H), 4.56 (dd, J=3.1, 11.3 Hz, 1H), 6.13 (d, J=3.5 Hz, 1H), 6.17 (d, 3.5Hz, 1H), 6.65 (brs, 1H), 7.22-7.43 (m, 10H), 7.81 (brs, 1H), 7.92 (brs,1H). MS Calcd.: 430; Found 431 (M+H).

Step E

4,4-Dimethyl-8-[5-(1-methyl-1-phenyl-ethyl)-[1,3,4]oxadiazol-2-yl]-2-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidine(5): Compound 4 (0.060 g, 0.14 mmol) was diluted in POCl₃ (3 mL). Thesolution was heated to 75° C. for 3 h. The solution was cooled andcarefully quenched with water. The solution was diluted with AcOEt andthe mixture carefully neutralized with sat. NaHCO₃. The organic layerwas separated and the aqueous layer was extracted twice more with AcOEtportions. The combined organic layers were dried (Na₂SO₄), concentrated,and flash chromatographed to give the desired product as a white solid.0.016 g obtained (28% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.55 (s, 6H),1.80 (s, 6H), 2.02-2.16 (m, 2H), 4.68 (dd, J=3.2, 11.6 Hz, 1H), 6.23 (d,J=3.2 Hz, 1H), 6.30 (d, J=3.2 Hz, 1H), 7.20-7.46 (m, 10H). MS Calcd.;412; Found 413 (M+H).

Example 11373-Methyl-2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylicacid [1-ethyl-1-(4-trifluoromethyl-phenyl)-propyl]-amide

Step A

5-Amino-1-(1-methyl-2-oxo-2-phenyl-ethyl)-1H-pyrazole-4-carboxylic acidethyl ester (1): 5-Amino-1H-pyrazole-4-carboxylic acid ethyl ester (7.35g, 47.3 mmol) was dissolved in 160 mL of DMF. Na₂CO₃ (5.02 g, 47.3 mmol)was added followed by 2-bromopropiophenone (7.2 mL, 47.3 mmol). Thereaction stirred at room temperature for 2 days. The solution wasdiluted with AcOEt and the organic layer was washed with sat. NaHCO₃,brine, dried (MgSO₄), and concentrated. Flash chromatography (20-45%AcOEt/hexane) gave the desired product (1.58 g, 12% yield). ¹H NMR (400MHz, CDCl₃) δ 1.3 (t, J=7.0 Hz, 3H), 1.7 (d, J=7.4 Hz, 3H), 4.2 (q,J=7.0 Hz, 2H), 5.4 (bs, 2H), 5.9 (q, J=7.0 Hz, 1H), 7.41-7.59 (m, 3H),7.60 (s, 1H), 8.0 (d, J=8.0 Hz, 2H).

Step B

5-Amino-1-(2-hydroxy-1-methyl-2-phenyl-ethyl)-1H-pyrazole-4-carboxylicacid ethyl ester (2): Compound 1 (0.7 g, 2.43 mmol) was dissolved in 34mL EtOH. NaBH₄ (0.18 g, 4.87 mmol) was added in one shot. The reactionstirred at room temperature for 0.5 h. The solution was quenched withsat. NH₄Cl and extracted with CH₂Cl₂ (3 times). The organic layer waswashed with brine, dried (MgSO₄), concentrated to give a fluffy whitesolid 2 (0.69 g, 98% yield). MS: Calcd.: 289; Found: 290 (M+H).

Step C

3-Methyl-2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylicacid ethyl ester (3): Compound 2 (0.80 g, 2.8 mmol) was dissolved inCH₂Cl₂. SOCl₂ (0.61 mL, 8.3 mmol) was added dropwise. After 90 minutes,the solution was concentrated to give a yellow solid. After pumping onhigh vacuum for 5 minutes, the solid was dissolved in CHCl₃. Et₃N (2.7mL, 19.5 mmol) was added dropwise and the reaction mixture stirred for 1hour. The reaction was quenched with water and diluted with AcOEt. Thesolution was washed with sat. NH₄Cl, sat. NaHCO₃, brine, and then dried(MgSO₄). Flash chromatography (20% AcOEt/hexane) gave both the syn (0.10g, 14%) and anti (0.62 g, 82%) isomers 3. Anti isomer ¹H NMR (400 MHz,CDCl₃) δ 1.23 (t, J=7.0 Hz, 3H), 1.80 (d, J=6.6 Hz, 3H), 4.10-4.20 (m,2H), 4.25-4.35 (m, 1H), 4.38 (brs, 1H), 5.10 (d, J=9.8 Hz, 1H),7.17-7.25 (m, 5H), 7.59 (s, 1H). Syn isomer ¹H NMR (400 MHz, CDCl₃) δ1.28 (d, J=7.0 Hz, 3H), 7.38 (t, J=7.4 Hz, 3H), 4.25-4.35 (m, 2H),7.43-7.52 (m, 1H), 5.17 (brs, 1H), 5.23 (d, J=9.8 Hz, 1H), 7.37-7.45 (m,5H).

Step D and E

3-Methyl-2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylicacid [1-ethyl-1-(4-trifluoromethyl-phenyl)-propyl]-amide (5):

Compound 3 (0.085 g, 0.3 mmol) was dissolved in EtOH (3 mL). KOH (6M inwater, 0.9 mL, 1.78 mmol) was added. The reaction stirred at 60° C. for3 h. The solution was cooled, diluted with AcOEt (10 mL) and water (10mL) and shaken vigorously. The Aqueous layer was separated and acidifiedto pH=3. This acidic layer was then extracted with AcOEt (3 times). Thecombined AcOEt layers were washed with brine, dried (Na₂SO₄) andconcentrated. The residue was then dissolved in NMP (1 mL) and1-ethyl-1-(4-trifluoromethyl-phenyl)-propylamine (0.087 g, 0.37 mmol),HATU (0.14 g, 0.37 mmol), and DIEA (0.14 mL, 0.78 mmol) were added. Thereaction was heated to 80° C. for 2 days. The solution was then cooled,washed with water, dried (MgSO₄), and concentrated. Flash chromatography(20% AcOEt/hexanes) gave 0.017 g (12% yield) of amide 5.

¹H NMR (400 MHz, CDCl₃) δ 0.79-0.83 (m, 6H), 1.26 (d, J=7.0 Hz, 3H),1.99-2.05 (m, 2H), 2.23-2.31 (m, 2H), 4.44-4.48 (m, 1H), 5.19 (brs, 1H),5.24 (d, J=10 Hz, 1H), 5.66 (brs, 1H), 7.37-7.63 (m, 9H). MS Calcd.:456; Found: 457 (M+H).

Example 11388-Methyl-5-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5,a][1,3]diazepine-3-carboxylicacid (1-methyl-1-phenyl-ethyl)-amide

Step A

5-Amino-1-[4-tert-butyl-dimethyl-silanyloxy]-1-methyl-4-phenyl-butyl]-1H-pyrazole-4-carboxylicacid ethyl ester (1):

5-Amino-1H-pyrazole-4-carboxylic acid ethyl ester (1.60 g, 10.3 mmol)was dissolved in 10 mL of DMF. The solution was cooled to 0° C. and NaH(60% in mineral oil, 0.82 g, 20.6 mmol) was added in one portion. Thereaction warmed to room temperature after H₂ evolution ceased. Thereaction stirred for 0.5 h till a bright orange color persisted. Thereaction was again brought to 0° C. and methanesulfonic acid4-(tert-butyl-dimethyl-silanyloxy)-1-methyl-4-phenyl-butyl ester (3.49g, 9.38 mmol) was then added as a solution in 6 mL DMF. The reactionwarmed to room temperature and stirred for 2.5 days. The solution wasquenched with water and diluted with AcOEt. The organic layer wasseparated and the aqueous layer was extracted twice more with AcOEt. Thecombined organic layers were dried (MgSO₄), concentrated and flashchromatographed (15% AcOEt/hexanes) to give 0.530 g (13% yield) of thedesired product as an oil. ¹H NMR (400 MHz, CDCl₃) δ 0.16 (s, 3H), 0.17(s, 3H), 1.04 (d, J=10 Hz, 9H), 1.48-1.52 (m, 3H), 1.55 (d, J=6.4 Hz,3H), 1.60 (d, J=6.8 Hz, 3H—other diastereomer), 1.62-1.75 (m, 2H),1.97-2.07 (m, 2H), 2.10-2.20 (m, 2H—other diastereomer), 4.02-4.07 (m,1H), 4.21-4.29 (m, 1H—other diastereomer), 4.40-4.43 (m, 2H), 4.79-4.86(m, 1H), 5.04 (brs, 1H), 5.25 (brs, 1H—other diastereomer), 7.36-7.47(m, 5H), 7.79 (s, 1H); MS Calcd.: 431; Found 432 (M+H).

Step B and C

8-Methyl-5-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5,a][1,3]diazepine-3-carboxylicacid ethyl ester (3): Compound 1 (2.0 g, 4.6 mmol) was dissolved in 9 mLTHF. TBAF (1M in THF, 13.9 mL, 13.9 mmol) was added at room temperature.The reaction stirred for 0.5 h. The reaction was diluted with ether andwashed with brine and water. The ether layer was dried (MgSO₄) andconcentrated to give the crude alcohol product 2. MS Cald.: 317; Found318 (M+H).

Alcohol 2 was taken up in CH₂Cl₂ (80 mL). SOCl₂ (1.7 mL, 23.4 mmol) wasadded. After 1 h, the solution was concentrated and re-dissolved in 80mL DMF. CsCO₃ (12.6 g, 39 mmol) was added. After 3 h, additional CsCO₃(12.6 g, 39 mmol) was added. The reaction ran 1.5 days. The reaction wasquenched with water and diluted with AcOEt. After separation of theorganic layer, the aqueous layer was washed twice with AcOEt. Thecombined organic layers were dried (MgSO₄), concentrated, and flashchromatographed to give 0.35 g (26% yield) of a mixture of cis and transisomers which were readily separated.

Anti isomer—¹H NMR (400 MHz, CDCl₃) δ 1.24 (t, J=7.0 Hz, 3H), 1.40 (d,J=7.0 Hz, 3H), 1.93-2.34 (m, 4H), 4.05 (d, 1H), 4.09-4.23 (m, 2H),4.79-4.85 (m, 1H), 6.40 (bs, 1H), 7.27-7.44 (m, 5H), 7.64 (s, 1H). MSCalcd.: 299; Found 300 (M+H). Syn isomer—¹H NMR (400 MHz, CDCl₃) δ 1.24(t, J=7.0 Hz, 3H), 1.68 (d, J=7.0 Hz, 3H), 1.70-1.80 (m, 1H), 2.00-2.23(m, 3H), 4.17-4.30 (m, 4H), 6.43 (brs, 1H), 7.22-7.40 (m, 5H), 7.63 (s,1H). MS Calcd.: 299; Found 300 (M+H).

Step D

8-Methyl-5-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5,a][1,3]diazepine-3-carboxylicacid (1-methyl-1-phenyl-ethyl)-amide (4): Compound 3 (0.074 g, 0.25mmol) was diluted with EtOH (0.8 mL). KOH (6M in water, 0.23 mL) wasadded and the reaction stirred at 60° C. for 3.5 h. The solution wascooled and diluted with AcOEt and water. After vigorous shaking, theaqueous layer was removed and acidified to pH=3. The aqueous layer wasthen extracted with AcOEt (3 times). The organic layers were combined,dried (MgSO₄), and concentrated to give 0.070 g of desired carboxylicacid. MS Calcd.: 271; Found 272 (M+H).

This acid residue (0.070 g, 0.26 mmol) was dissolved in NMP (2 mL). HATU(0.12 g, 0.31 mmol) and cumylamine (0.042 g, 0.31 mmol) were addedfollowed by DIEA (0.090 mL, 0.52 mmol). The reaction stirred at 90° C.for 2 h. The solution was cooled to room temperature and diluted withwater. The solution was extracted from AcOEt (3 times), dried (MgSO₄),and concentrated. Flash chromatography (30% AcOEt/hexanes) gave thedesired product. 0.065 g obtained (65% yield). ¹H NMR (400 MHz, CDCl₃) δ1.65 (d, J=6.6 Hz, 3H), 1.71 (s, 3H), 1.75 (s, 3H), 2.00-2.21 (m, 4H),4.21-4.29 (m, 2H), 5.80 (brs, 1H), 7.02 (brs, 1H), 7.18-7.47 (m, 10H),7.49 (s, 1H); MS Calcd.: 388; Found 389 (M+H).

Example 1142(1R,4S)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate

1) To a solution of 1 (0.4 g, 1.32 mmol) and DMF (1 drop) in toluene (4mL) was added SOCl₂ (0.31, 2.64 mmol) at room temperature. Afterstirring at 60° C. 1 h, the solvent was concentrated in vacuo. Theresidue was diluted with toluene, and borneol (0.3 g, 1.98 mmol) andEt₃N (0.3 g, 2.90 mmol) was added there to. After stirring at 60° C. 1h, the reaction mixture was washed with 1N HCl and brine, dried overMgSO₄, and concentrated in vacuo. Flash chromatography to give thedesired product as oil. To a stirred solution of the oil obtained (90mg, 0.2 mmol) in AcOEt (2 mL) was added 4M HCl-AcOEt (0.5 mL, 2.0 mmol)at room temperature. The precipitate was collected by filtration to give2 as HCl salt. MS Calcd.: 440; Found 441 (M+H).

Compounds of Examples 1139-1141 shown in the Table 16, were prepared ina manner similar to that described in Example 1142.

TABLE 16 1139

1-propyl-1-(4- (trifluoromethyl)phenyl)butyl 7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate MS (ESI,m/z) 514 (M + H)⁺ 1140

(2R,5S)-2-isopropyl-5- methylcyclohexyl 7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxylate mp 123-124° C. 1141

(1R,4S)-1 3,3- trimethylbicyclo[2.2.1]hept-2-yl2,7,7-trimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate mp 149-150° C. HCl salt

Compounds of Examples 868-923 and 1143-1146 shown in the table 6, wereprepared from compound of Examples 35 in a manner similar to thatdescribed in followed reference 1˜6.

-   1) Poulan R F., Tartar A L., Deprez B p., Tetrahedron Lett. 2001,    42, 1495.-   2) Rigo B., Cauliesz P., Fasseur D., Couturier D., Synthetic    Communications 1986, 16, 1665.-   3) Carlsen H J., Jorgensen K B., J. Heterocyclic Chem., 1994, 31,    805.-   4) Kiryanov A A., Sampson P., Seed J., J. Org. Chem., 2001, 66,    7925.-   5) Kelly T R., Lang F R., Tetrahedron Lett., 1995, 36, 5319.-   6) Walia J S., Walia A S., Lankin D C., Petterson R C., Singh J., J.    Heterocyclic Chem., 1985, 22, 1117.

TABLE 6 Example Structure Name Physiological Data 868

7,7-dimethyl-3-(5-(1-methyl-1- phenylethyl)-1,3,4-oxadiazol-2-yl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI,m/z) 414 (M + H)⁺ 869

7,7-dimethyl-3-(3-(1-methyl-1- phenylethyl)-1,2,4-oxadiazol-5-yl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI,m/z) 414 (M + H)⁺ 870

3-(5-(1-(4-chlorophenyl)-1- methylethyl)-1,3,4-oxadiazol-2-yl)-7,7-dimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine MS (ESI, m/z) 449 (M + H)⁺ 871

3-(5-tert-butyl-1,3,4-oxadiazol- 2-yl)-7,7-dimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI, m/z) 352 (M + H)⁺ 872

7,7-dimethyl-5-phenyl-3-(5- phenyl-1,3,4-oxadiazol-2-yl)- 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI, m/z) 372 (M + H)⁺ 873

7,7-dimethyl-3-(5-methyl- 1,3,4-oxadiazol-2-yl)-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI, m/z) 310 (M + H)⁺ 874

7,7-dimethyl-3-(5-(1-methyl-1- phenylethyl)-1,3,4-thiadiazol-2-yl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI,m/z) 430 (M + H)⁺ 875

7,7-dimethyl-5-phenyl-3-(5- phenyl-1,3-oxazol-2-yl)- 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI, m/z) 371 (M + H)⁺ 876

7,7-dimethyl-5-phenyl-3-(4- phenyl-1,3-oxazol-2-yl)- 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI, m/z) 371 (M + H)⁺ 877

7,7-dimethyl-3-(4-(1-methyl-1- phenylethyl)-1,3-oxazol-2-yl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI, m/z) 413(M + H)⁺ 888

7,7-dimethyl-3-(5-(1-methyl-1- phenylethyl)-1,2,4-oxadiazol-3-yl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI,m/z) 414 (M + H)⁺ 889

3-(5-(1-(4-methoxyphenyl)-1- methylethyl)-1,3,4-oxadiazol-2-yl)-7,7-dimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine MS (ESI, m/z) 444 (M + H)⁺ 890

7,7-dimethyl-3-(5-(1-methyl-1- (2-pyridinyl)ethyl)-1,3,4-oxadiazol-2-yl)-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidineMS (ESI, m/z) 415 (M + H)⁺ 891

7,7-dimethyl-3-(5-(1-methyl-1- (4-pyridinyl)ethyl)-1,3,4-oxadiazol-2-yl)-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidineMS (ESI, m/z) 415 (M + H)⁺ 892

3-(5-(1-(4-iodophenyl)-1- methylethyl)-1,3,4-oxadiazol-2-yl)-7,7-dimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine MS (ESI, m/z) 540 (M + H)⁺ 893

7,7-dimethyl-3-(5-(1-methyl-1- (3-pyridinyl)ethyl)-1,3,4-oxadiazol-2-yl)-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidineMS (ESI, m/z) 415 (M + H)⁺ 894

3-(5-isopropyl-1,3,4-oxadiazol- 2-yl)-7,7-dimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI, m/z) 338 (M + H)⁺ 895

3-(5-(4-chlorobenzyl)-1,3,4- oxadiazol-2-yl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI, m/z) 421(M + H)⁺ 896

ethyl 4-(1-(5-(7,7-dimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-1,3,4- oxadiazol-2-yl)-1- methylethyl)benzoate MS(ESI, m/z) 486 (M + H)⁺ 897

7,7-dimethyl-3-(5-(1-methyl-1- phenylethyl)-1,3-oxazol-2-yl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI, m/z) 413(M + H)⁺ 898

7,7-dimethyl-3-(5-(1-methyl-1- (4-methylphenyl)ethyl)-1,3,4-oxadiazol-2-yl)-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidineMS (ESI, m/z) 414 (M + H)⁺ 899

3-(5-(1-(4-methoxyphenyl)-1- methylethyl)-1,3,4-oxadiazol-2-yl)-7,7-dimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine MS (ESI, m/z) 444 (M + H)⁺ 900

2-(4-(1-(5-(7,7-dimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-1,3,4- oxadiazol-2-yl)-1- methylethyl)phenyl)-2-propanol MS (ESI, m/z) 472 (M + H)⁺ 901

N-((7,7-dimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3- yl)(imino)methyl)-2-methyl-2- phenylpropanamide MS (ESI,m/z) 416 (M + H)⁺ 902

3-(4,4-dimethyl-6-phenyl-1,4- dihydro-2-pyrimidinyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI,m/z) 412 (M + H)⁺ 903

7,7-dimethyl-3-(5-(1-methyl-1- (4-methylphenyl)ethyl)-1,3,4-thiadiazol-2-yl)-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidineMS (ESI, m/z) 444 (M + H)⁺ 904

7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboximidamide MS (ESI, m/z) 270 (M + H)⁺ 905

3-(4-(4-fluorophenyl)-1H- imidazol-2-yl)-7,7-dimethyl-5- phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI, m/z) 388 (M + H)⁺ 906

N-((7,7-dimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3- yl)(imino)methyl)-2-ethyl-2-(4- methylphenyl)butanamideMS (ESI, m/z) 458 (M + H)⁺ 907

3-(4,4-dimethyl-6-(4- methylphenyl)-1,4-dihydro-2-pyrimidinyl)-7,7-dimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine MS (ESI, m/z) 426 (M + H)⁺ 908

7,7-dimethyl-N-(((1-methyl-1- phenylethyl)amino)carbonyl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3-carboximidamide MS (ESI, m/z) 431 (M + H)⁺ 909

7,7-dimethyl-5-phenyl-N- ((((1S)-1- phenylethyl)amino)carbonyl)-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine-3- carboximidamide MS(ESI, m/z) 417 (M + H)⁺ 910

7,7-dimethyl-3-(1-methyl-5-(1- methyl-1-phenylethyl)-1H-imidazol-2-yl)-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidineMS (ESI, m/z) 427 (M + H)⁺ 911

3-(5-(1-ethyl-1-(4- methylphenyl)propyl)-1,3,4-oxadiazol-2-yl)-7,7-dimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine MS (ESI, m/z) 457 (M + H)⁺ 912

7,7-dimethyl-3-(3-(1-methyl-1- phenylethyl)-1H-1,2,4-triazol-5-yl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI,m/z) 414 (M + H)⁺ 913

3-(4,4-dimethyl-6-(4- methylphenyl)-1,4,5,6-tetrahydro-2-pyrimidinyl)-7,7- dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI, m/z) 428 (M + H)⁺ 914

7,7-dimethyl-3-(3-(1-methyl-1- (4-methylphenyl)ethyl)-1H-pyrazol-5-yl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine MS(ESI, m/z) 426 (M + H)⁺ 915

3-(5-(1-ethyl-1-(4- iodophenyl)propyl)-1,3,4-oxadiazol-2-yl)-7,7-dimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine MS (ESI, m/z) 568 (M + H)⁺ 916

3-(5-(1-(4-chlorophenyl)-1- ethylpropyl)-1,3,4-oxadiazol-2-yl)-7,7-dimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidineMS (ESI, m/z) 476 (M + H)⁺ 917

ethyl 4-(1-(5-(7,7-dimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-1,3,4- oxadiazol-2-yl)-1- ethylpropyl)benzoate MS(ESI, m/z) 514 (M + H)⁺ 918

7,7-dimethyl-3-(4-methyl-5-(1- methyl-1-phenylethyl)-4H-1,2,4-triazol-3-yl)-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine MS (ESI, m/z) 427 (M + H)⁺ 919

7,7-dimethyl-3-(1-methyl-3-(1- methyl-1-phenylethyl)-1H-1,2,4-triazol-5-yl)-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine MS (ESI, m/z) 427 (M + H)⁺ 920

3-(5-(1-ethyl-1-(4- methoxyphenyl)propyl)-1,3,4-oxadiazol-2-yl)-7,7-dimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine MS (ESI, m/z) 472 (M + H)⁺ 921

7,7-dimethyl-3-(1-methyl-3-(1- methyl-1-(4- methylphenyl)ethyl)-1H-pyrazol-5-yl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidine MS(ESI, m/z) 440 (M + H)⁺ 922

3-(5-(1-ethyl-1-(4- methylphenyl)propyl)-1,3,4-thiadiazol-2-yl)-7,7-dimethyl-5- phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine MS (ESI, m/z) 472 (M + H)⁺ 923

3-(5-(1-(4-chlorophenyl)-1- ethylpropyl)-1,3,4-thiadiazol-2-yl)-7,7-dimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5- a]pyrimidineMS (ESI, m/z) 492 (M + H)⁺ 1143

(5R)-3-(5-(1-ethyl-1-(4- methylphenyl)propyl)-1,3,4-thiadiazol-2-yl)-2,7,7-trimethyl- 5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine mp 132-134° C. 1144

(5R)-3-(5-(1-ethyl-1-(4- methylphenyl)propyl)-1,3,4-oxadiazol-2-yl)-2,7,7-trimethyl- 5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine MS (ESI, m/z) 470 (M + H)⁺ 1145

(5R)-3-(5-(1-ethyl-1- phenylpropyl)-1,3,4-thiadiazol-2-yl)-2,7,7-trimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine mp 174-175° C. 1146

(5R)-3-(5-(1-ethyl-1- phenylpropyl)-1,3,4-oxadiazol-2-yl)-2,7,7-trimethyl-5-phenyl- 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine MS (ESI, m/z) 456 (M + H)⁺

Experiment 1

Strategy for cloning of the cDNAs encoding the human CaR

Strategy for cloning of the cDNAs encoding the human CaR is shown below.To amplify the cDNA encoding the N-terminal moiety of the human CaR, thesynthetic DNA primers, Cal-U:5′-AGAGTCGACGCCACCATGGCATTTTATAGCTGCTGCTGG-3′ andCal-L:5′-AAATGAGCTCTCGGTTGGTGGCCTTGAC-3′, were constructed. In thiscase, SalI site was added at the 5′ end of amplified cDNA. To amplifythe cDNA encoding the C-terminal moiety of the human CaR, the syntheticDNA primers, Ca2-U: 5′-AAACGAGCTCTCCTACCTCCTCCTCTTC-3′ and Ca2-L:5′-TCTGCGGCCGCTCCCTAGCCCAGTCTTCTCCTTCC-3′, were constructed. In thiscase, NotI site was added at the 3′ end of amplified cDNA. PCR wascarried out by Hot Start method. The reaction solution of the upperphase was added of 1 pg of the human kidney-derived cDNA (TOYOBO), 0.3mM dNTPs and 2.5 unit LA Taq DNA polymerase (Takara shuzo co.) andfilled up to 30 μl with water and buffer attached to the enzyme. To thereaction solution of the lower phase was added 12.5 μM each of thesynthetic primers and 0.5 mM dNTPs and filled up to 20 μl with water andbuffer attached to the enzyme. The reaction solution of the upper phasewas added on the lower phase covered with an AmpliWax PCR Gem100 (TakaraShuzo Co.). The samples were subject to PCR amplification using aThermal Cycler (Perkin-Elmer Co.). The amplified cDNAs were confirmed byagarose gel electrophoresis.

Experiment 2

Preparation of CaR-Expression CHO Cells

The PCR products obtained in Experiment 1 were separated by agarose gelelectrophoresis. The PCR products were excised and purified from the geland subcloned into pT7Blue-T vector (Takara Shuzo Co.). The cDNAfragment encoding the N-terminal moiety of the human CaR was releasedfrom the subcloned pT7Blue-T vector treated with SalI and SacI. The cDNAfragment encoding the C-terminal moiety of the human CaR was releasedfrom the subcloned pT7Blue-T vector treated with SacI and NotI. UsingDNA Ligation kit (Takara Shuzo Co.), these fragments were insertedbetween the site of SalI- and NotI- in the digested pMSRαneo vector.Thus, the pMSRαneo-CaR for animal cell expression was constructed.

Ten μg of the pMSRαneo-CaR was added to the solution containing 8×10⁶CHO—K1 cells, and transfection was carried out using Gene Pulser (0.4 cmcuvette, 0.25 kV, 960 mF) (Bio-Rad Laboratories). The cells werecultured in HamF12 containing 10% fetal calf serum for one day. Afterpassage, the cells were cultured in HamF12 containing 10% fetal and 500μg/ml Genetisine. The cells were seeded on 96-well plate in 1×10³cells/well and transformants, CaR-expressing CHO cells, were selected inthe selection medium.

Experiment 3

Selection of the CaR-Expressing CHO Cell Line by Calcium MobilizationAssay

A method for calcium mobilization assay is shown below. TheCaR-expressing CHO cells were seeded on a 96-well white plate in 2×10⁴cells/well, followed by cultivation for 48 hours. After washing thecells with Phosphate-Buffered Saline, 100 μl of buffer solution (120 mMNaCl, 22 mM NaHCO₃, 6 mM KCl, 0.2 mM CaCl₂, 1 mM MgCl₂, 5 mM glucose, 5mM HEPES (pH 7.4)) containing 5 μM FuraPE3AM (Texas FluorescenceLaboratories) was added to the wells and kept at 37° C. for 1 hour. Thecells were washed twice with Phosphate-Buffered Saline. After adding 180μl of the reaction buffer solution (130 mM NaCl, 5.4 mM KCl, 0.2 mMCaCl₂, 0.9 mM MgCl₂, 10 mM glucose, 20 mM HEPES (pH 7.4)) to the wells,20 μl of 60 mM CaCl₂ was added and intracellular calcium concentrationwere measured with a fluorometric imaging plate reader (FDSS 2000,Hamamatsu photonics). One clone increasing intracellular calciumconcentration was selected and used for the following experiment.

Experiment 4

GTPγS Binding Assay

Preparation of Membrane Fraction is Described Below.

The human CaR-expressing CHO cells were inoculated to a F500 flask in1.8×10⁵ cells/flask followed by cultivation for 2 days. The cells werescraped with 10 ml of Phosphate-Buffered Saline containing 0.02% EDTA.After centrifugation (2000 rpm, 10 min) of the cells, the cell pelletwas resuspended into 12 ml of homogenate buffer solution (10 mM NaHCO₃,1 mM EDTA, 1× Protease inhibitor cocktail (pH 7.4)) and homogenized byPolytron™ (20000 rpm, 1 min). The cell debris was removed bycentrifugation (2000 rpm, 10 min), and then the CaR-expressing cellmembrane fraction was collected by ultracentrifugation (Beckman 70 Titype rotor, 30000 rpm, 1 hour).

The GTPγS binding activity was measured as follows. Twenty μg of theCaR-expressing cell membrane was incubated with test compounds for 10min. The assays were carried out at room temperature for an hour in areaction solution mixture containing 20 mM HEPES (pH. 7.4), 100 mM NaCl,1 mM MgCl₂, 167 μg/ml DTT, 5 μM guanosine 5′-diphosphate, 0.4 nM[³⁵S]-guanosine 5′-(γ-thio) triphosphate ([³⁵S]-GTPγS) and 6 mM CaCl₂.The mixture was filtered through a GF/C filter. After washing fourthwith 300 μl of Phosphate-Buffered Saline, the amount of [³⁵S]-GTPγSbound to the filter was measured using a Top-count scintillationcounter.

Effects of test compounds on [³⁵S]-GTPγS binding were expressed inpercentage terms. This was calculated from the equation[100×(t′−b)]/(t−b) where t′, t and b are values of [³⁵S]-GTPγS binding(dpm), t′ in the presence of 6 mM calcium and the test compound, t inthe presence of 6 mM calcium only and b in the absence of both 6 mMcalcium and the test compound.

The antagonist dose-dependently decreased [³⁵S]-GTPγS binding inmembrane preparation. The agonist dose-dependently increased [³⁵S]-GTPγSbinding in membrane preparation.

The results are shown in Table 7.

TABLE 7 Ex. No. [³⁵S]-GTP γ S binding (%) 318* 34 (1 μM) 335* 0 (1 μM)310* 0 (1 μM) 312* 10 (1 μM) 436* 12 (1 μM) 423* 0 (1 μM)  111** 256 (10μM) *antagonist **agonist

INDUSTRIAL APPLICABILITY

Compound (I), (II), (III) or (IIIa) of the present invention has anexcellent Ca receptor modulating activity and enhances the secretion ofPTH, and therefore useful as drugs for treating bone diseases,kidney-acting drugs, central nervous system and endocrine-acting drugs,digestive system-acting drugs, and the like.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20090215746A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A compound of the formula (II):

wherein ring A is an optionally substituted 5- to 7-membered ring; Q isC, CR⁵ (wherein R⁵ is H, an optionally substituted hydrocarbon group, anoptionally substituted hydroxyl group, an optionally substituted aminogroup, an optionally substituted thiol group, cyano group, a halogenatom, an optionally substituted heterocyclic group, or a group of theformula: -Z¹-Z² (wherein -Z¹- is —CO—, —CS—, —SO— or —SO₂—, and Z² is anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group, an optionally substituted hydroxyl group, or anoptionally substituted amino group)), or N; X¹ is CR¹ (wherein R¹ is H,an optionally substituted hydrocarbon group, an optionally substitutedhydroxyl group, an optionally substituted amino group, an optionallysubstituted thiol group, cyano group, a halogen atom, an optionallysubstituted heterocyclic group, or a group of the formula: -Z¹-Z²(wherein -Z¹- and Z² are as defined above)), CR¹R² (wherein R¹ is asdefined above, and R² is H, or an optionally substituted hydrocarbongroup), N, or NR¹³ (wherein R¹³ is H, an optionally substitutedhydrocarbon group, an optionally substituted hydroxyl group, anoptionally substituted amino group, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above)); R³ is H, an optionally substitutedhydrocarbon group, an optionally substituted hydroxyl group, anoptionally substituted amino group, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above); Y is C, CR⁴ (wherein R⁴ is H, an optionallysubstituted hydrocarbon group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substituted thiolgroup, cyano group, a halogen atom, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above)), or N; Ar is an optionally substituted cyclicgroup; R⁹ and R¹⁰ are the same or different and are H, an optionallysubstituted hydrocarbon group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substituted thiolgroup, cyano group, a halogen atom, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above); and R¹¹ and R¹² are the same or different andare H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, cyano group, a halogen atom, anoptionally substituted heterocyclic group, or a group of the formula:-Z^(1′)-Z² (wherein -Z^(1′)- is —CS—, —SO— or —SO₂—, and Z² is asdefined above); or R⁹ and R¹⁰, or R¹¹ and R¹² may be combined to form anoxo group, methylene group or a ring; or R¹⁰ and R¹¹ may be combined toform a ring; and

is a single bond or a double bond; provided that (1) when ring A is a6-membered ring and Q is C or CR⁵, X¹ is C-Z¹-Z², C(-Z¹-Z²)R² orN-Z¹-Z², and both R⁹ and R¹⁰ are not H, or R⁹ and R¹⁰ are not combinedto form an oxo group, or R¹⁰ and R¹¹ are not combined to form a5-membered ring, (2) when ring A is a 6-membered ring and Q is N, X¹ isC-Z¹-Z², C(-Z¹-Z²)R² or N-Z¹-Z², and R⁹ and R¹⁰ are not combined to forman oxo group, (3) when ring A is a 5-membered ring and Q is C or CR⁵, X¹is C-Z¹-Z², C(-Z¹-Z²)R² or N-Z¹-Z², and Z² is an optionally substitutedamino group, and (4) when ring A is a 5-membered ring and Q is N, atleast one of R⁹ and R¹⁰ is CHR¹⁵R¹⁶ (wherein at least one of R¹⁵ and R¹⁶are the same or different and are H, an optionally substitutedhydrocarbon group, an optionally substituted hydroxyl group, anoptionally substituted amino group, an optionally substituted thiolgroup, a halogen atom, an optionally substituted heterocyclic group, ora group of the formula: -Z¹-Z² (wherein -Z¹- and Z² are as definedabove)) and the other is other than an optionally substituted phenylgroup; or a salt thereof.
 2. A compound of the formula (III):

wherein R^(□) is H, an optionally substituted hydrocarbon group, anoptionally substituted hydroxyl group, an optionally substituted thiolgroup, an optionally substituted amino group, cyano group, a halogenatom, an optionally substituted heterocyclic group, or a group of theformula: -Z¹-Z² (wherein -Z¹- is —CO—, —CS—, —SO— or —SO₂—, and Z² is anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group, an optionally substituted hydroxyl group, or anoptionally substituted amino group); R³ is H, an optionally substitutedhydrocarbon group, an optionally substituted hydroxyl group, anoptionally substituted amino group, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above); Y is C, CR⁴ (wherein R⁴ is H, an optionallysubstituted hydrocarbon group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substituted thiolgroup, cyano group, a halogen atom, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above)) or N; R⁸ is H, an optionally substitutedhydrocarbon group, an optionally substituted hydroxyl group, anoptionally substituted amino group, an optionally substituted thiolgroup, cyano group, a halogen atom, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above); Ar is an optionally substituted cyclic group;R⁹ and R¹⁰ are the same or different and are H, an optionallysubstituted hydrocarbon group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substituted thiolgroup, cyano group, a halogen atom, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above), or R⁹ and R¹⁰ may be combined to form an oxogroup, methylene group or a ring; X³ is a bond, oxygen atom, anoptionally oxidized sulfur atom, N, NR^(7′) (wherein R^(7′) is H, anoptionally substituted hydrocarbon group, an optionally substitutedhydroxyl group, an optionally substituted amino group, an optionallysubstituted heterocyclic group, or a group of the formula -Z^(1′)-Z²(wherein -Z^(1′)- is —CS—, —SO— or —SO₂—, and Z² is as defined above)),or an optionally substituted bivalent C₁₋₂ hydrocarbon group; and

is a single bond or a double bond; provided that at least one of R⁹ andR¹⁰ is CHR¹⁵R¹⁶ (wherein R¹⁵ and R¹⁶ are the same or different and areH, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, a halogen atom, an optionallysubstituted heterocyclic group, or a group of the formula: -Z¹-Z²(wherein -Z¹- and Z² are as defined above)) and the other is other thanan optionally substituted phenyl group; or a salt thereof.
 3. Thecompound according to claim 1, wherein R¹ is (1) an optionallysubstituted heterocyclic group, or (2) a group of the formula: -Z¹-Z²(wherein -Z¹- is —CO—, —CS—, —SO— or —SO₂—, and Z² is an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup, an optionally substituted hydroxyl group, or an optionallysubstituted amino group).
 4. The compound according to claim 3, whereinZ¹ is —CO— and Z² is an optionally substituted hydroxyl group or anoptionally substituted amino group.
 5. The compound according to claim2, wherein R³ is H, a C₁₋₆ alkyl group or a C₇₋₁₄ aralkyl group.
 6. Thecompound according to claim 2, wherein R⁸ is H, a C₁₋₆ alkyl group, aC₁₋₆ alkylthio group or a C₁₋₆ alkoxy group which may be substitutedwith hydroxyl group.
 7. The compound according to claim 1, wherein R⁹and R¹⁰ are the same or different and are a C₁₋₆ alkyl group or R⁹ andR¹⁰ are combined each other to form a ring.
 8. The compound according toclaim 2, wherein R¹ is a group of the formula: -Z¹-Z² (wherein -Z¹- is—CO—, —CS—, —SO— or —SO₂—, and Z² is an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, anoptionally substituted hydroxyl group, or an optionally substitutedamino group); R³ is H; Ar is an optionally substituted aromatic ringgroup; X³ is CR¹¹R¹² (wherein R¹¹ and R¹² are the same or different andare H, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, cyano group, a halogen atom, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- and Z² are as defined above), or R¹¹ and R¹² may becombined to form an oxo group, methylene group or a ring); and R⁹ andR¹⁰ are the same or different and a C₁₋₆ alkyl group, or R⁹ and R¹⁰ maybe combined to form a ring.
 9. The compound according to claim 8,wherein R¹ is an optionally substituted carbamoyl group.
 10. Thecompound according to claim 9, wherein R¹ is a group of the formula:—CONR²⁰(CR²¹R²²R²³) (wherein R²⁰ is H or an optionally substitutedhydrocarbon group, and R²¹, R²², and R²³ are the same or different andare an optionally substituted hydrocarbon group or an optionallysubstituted heterocyclic group, or R²⁰ and R²¹ may be combined to form aring).
 11. A compound of the formula (IIIa):

wherein R^(1a) is (1) an optionally substituted heterocyclic group, or(2) a group of the formula: -Z^(1a)-Z^(2a) (wherein -Z^(1a)- is —CO—,—CS—, —SO— or —SO₂—, and Z^(2a) is (i) an optionally substitutedheterocyclic group, (ii) —NR^(20a)(CR^(21a)R^(22a)R^(23a)) (wherein (a)R^(20a) is H or an optionally substituted hydrocarbon group; and R^(21a)is an optionally substituted heterocyclic group which may be fused withan optionally substituted benzene ring, or an optionally substitutedphenyl group which may be fused with an optionally substituted aromaticheterocyclic ring and R^(22a) and R^(23a) are the same or different andare an optionally substituted hydrocarbon group or an optionallysubstituted heterocyclic group or R^(22a) and R^(23a) may be combined toform a ring, or (b) R^(20a) is H or an optionally substitutedhydrocarbon group; and R^(21a), R^(22a) and R^(23a) are the same ordifferent and are an optionally substituted C₁₋₈ aliphatic hydrocarbongroup, provided that the sum total of the number of carbon atoms is 7 ormore), (iii) —NR^(20a)R^(25a) (wherein R^(20a) is as defined above andR^(25a) is an optionally substituted C₆₋₁₀ aryl-C₂₋₄ alkyl, C₆₋₁₀aryloxy-C₂₋₄ alkyl, C₆₋₁₀ arylamino-C₂₋₄ alkyl, C₇₋₁₄ aralkylamino-C₂₋₄alkyl, heterocyclic ring-C₂₋₄ alkyl or heterocyclic group), (iv) asubstituted 5- to 7-membered cyclic amino group, or (v) —OR^(24a)(wherein R^(24a) is (a) an optionally substituted C₇₋₁₄ aralkyl group,(b) an optionally substituted C₃₋₇ alicyclic hydrocarbon group, (c) anoptionally substituted C₇₋₂₄ aliphatic hydrocarbon group, or (d) anoptionally substituted heterocyclic group); R³ is H, an optionallysubstituted hydrocarbon group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- is—CO—, —CS—, —SO— or —SO₂—, and Z² is an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, anoptionally substituted hydroxyl group, or an optionally substitutedamino group); Y is C, CR⁴ (wherein R⁴ is H, an optionally substitutedhydrocarbon group, an optionally substituted hydroxyl group, anoptionally substituted amino group, an optionally substituted thiolgroup, cyano group, a halogen atom, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above)) or N; R⁸ is H, an optionally substitutedhydrocarbon group, an optionally substituted hydroxyl group, anoptionally substituted amino group, an optionally substituted thiolgroup, cyano group, a halogen atom, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above); Ar is an optionally substituted cyclic group;R⁹ and R¹⁰ are the same or different and are H, an optionallysubstituted hydrocarbon group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substituted thiolgroup, cyano group, a halogen atom, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above), or R⁹ and R¹⁰ may be combined to form an oxogroup, methylene group or a ring; X³ is a bond, oxygen atom, anoptionally oxidized sulfur atom, N, NR^(7′) (wherein R^(7′) is H, anoptionally substituted hydrocarbon group, an optionally substitutedhydroxyl group, an optionally substituted amino group, an optionallysubstituted heterocyclic group, or a group of the formula -Z^(1′)-Z²(wherein -Z^(1′)- is —CS—, —SO— or —SO₂—, and Z² is as defined above)),or an optionally substituted bivalent C₁₋₂ hydrocarbon group; and

is a single bond or a double bond; provided that at least one of R⁹ andR¹⁰ is CHR¹⁵R¹⁶ (wherein R¹⁵ and R¹⁶ are the same or different and areH, an optionally substituted hydrocarbon group, an optionallysubstituted hydroxyl group, an optionally substituted amino group, anoptionally substituted thiol group, a halogen atom, an optionallysubstituted heterocyclic group, or a group of the formula: -Z¹-Z²(wherein -Z¹- and Z² are as defined above)) and the other is other thanan optionally substituted phenyl group; or a salt thereof.
 12. Thecompound according to claim 11, wherein R^(1a) is a group of theformula: —CONR^(20a)(CR^(21b)R^(22b)R^(23b)) (wherein R^(20a) is asdefined in claim 11 and at least one of R^(21b), R^(22b), and R^(23b) isan optionally substituted heterocyclic group which may be fused with anoptionally substituted benzene ring, or an optionally substituted phenylgroup which may be fused with an optionally substituted aromaticheterocyclic ring).
 13. The compound according to claim 11, whereinR^(1a) is (1) an optionally substituted 5- to 7-membered aromatic ornon-aromatic heterocyclic group having 1-4 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom, or (2) a group of theformula: —CO-Z^(2c) (wherein Z^(2c) is (i) an optionally substituted 5-to 7-membered aromatic or non-aromatic heterocyclic group having 1-4hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom,(ii) —NR^(20c)(CR^(21c)R^(22c)R^(23c)) (wherein (a) R^(20c) is H or anoptionally substituted hydrocarbon group selected from C₁₋₈ saturatedaliphatic hydrocarbon group, C₂₋₈ unsaturated aliphatic hydrocarbongroup, C₃₋₇ saturated alicyclic hydrocarbon group, C₃₋₇ unsaturatedalicyclic hydrocarbon group, C₉₋₁₀ partly saturated and fused bicyclichydrocarbon group, C₃₋₇ saturated or unsaturated alicyclic-C₁₋₈saturated or unsaturated aliphatic hydrocarbon group, C₉₋₁₀ partlysaturated and fused bicyclic hydrocarbon-C₁₋₄ alkyl group, C₉₋₁₀ partlysaturated and fused bicyclic hydrocarbon-C₂₋₄ alkenyl group, C₆₋₁₀ arylgroup and C₇₋₁₄ aralkyl group; and R^(21c) is 1) an optionallysubstituted 5- to 7-membered aromatic or non-aromatic heterocyclic grouphaving 1-4 hetero atoms selected from nitrogen atom, oxygen atom andsulfur atom, which may be fused with an optionally substituted benzenering, or 2) an optionally substituted C₆₋₁₀ aryl group which may befused with an optionally substituted 5- to 7-membered aromaticheterocyclic ring having 1-4 hetero atoms selected from nitrogen atom,oxygen atom and sulfur atom; and R^(22c) and R^(23c) are the same ordifferent and are an optionally substituted hydrocarbon group selectedfrom C₁₋₈ saturated aliphatic hydrocarbon group, C₂₋₈ unsaturatedaliphatic hydrocarbon group, C₃₋₇ saturated alicyclic hydrocarbon group,C₃₋₇ unsaturated alicyclic hydrocarbon group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon group, C₃₋₇ saturated or unsaturatedalicyclic-C₁₋₈ saturated or unsaturated aliphatic hydrocarbon group,C₉₋₁₀ partly saturated and fused bicyclic hydrocarbon-C₁₋₄ alkyl group,C₉₋₁₀ partly saturated and fused bicyclic hydrocarbon-C₂₋₄ alkenylgroup, C₆₋₁₀ aryl group and C₇₋₁₄ aralkyl group or an optionallysubstituted 5- to 7-membered aromatic or non-aromatic heterocyclic grouphaving 1-4 hetero atoms selected from nitrogen atom, oxygen atom andsulfur atom, or R^(22c) and R^(23c) may be combined to form a C₃₋₇carbon ring, or (b) R^(20c) is H or an optionally substitutedhydrocarbon group selected from C₁₋₈ saturated aliphatic hydrocarbongroup, C₂₋₈ unsaturated aliphatic hydrocarbon group, C₃₋₇ saturatedalicyclic hydrocarbon group, C₃₋₇ unsaturated alicyclic hydrocarbongroup, C₉₋₁₀ partly saturated and fused bicyclic hydrocarbon group, C₃₋₇saturated or unsaturated alicyclic-C₁₋₈ saturated or unsaturatedaliphatic hydrocarbon group, C₉₋₁₀ partly saturated and fused bicyclichydrocarbon-C₁₋₄ alkyl group, C₉₋₁₀ partly saturated and fused bicyclichydrocarbon-C₂₋₄ alkenyl group, C₆₋₁₀ aryl group and C₇₋₁₄ aralkylgroup; and R^(21c), R^(22c) and R^(23c) are the same or different andare an optionally substituted C₁₋₈ aliphatic hydrocarbon group, providedthat the sum total of the number of carbon atoms is 7 or more), (iii)—NR^(20c)R^(25c) (wherein R^(20c) is as defined above and R^(25c) is anoptionally substituted C₆₋₁₀ aryl-C₂₋₄ alkyl, C₆₋₁₀ aryloxy-C₂₋₄ alkyl,C₆₋₁₀ arylamino-C₂₋₄ alkyl, C₇₋₁₄ aralkylamino-C₂₋₄ alkyl, 5- to7-membered heterocyclic ring (having 1-4 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom)-C₂₋₄ alkyl or 5- to7-membered heterocyclic group having 1-4 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom), (iv) a substituted 5- to7-membered cyclic amino group, or (v) —OR^(24c) (wherein R^(24c) is (a)an optionally substituted C₇₋₁₄ aralkyl group, (b) an optionallysubstituted C₃₋₇ alicyclic hydrocarbon group, (c) an optionallysubstituted C₇₋₂₄ aliphatic hydrocarbon group, or (d) an optionallysubstituted 5- to 7-membered aromatic or non-aromatic heterocyclic grouphaving 1-4 hetero atoms selected from nitrogen atom, oxygen atom andsulfur atom; wherein said substituents for R^(1a), Z^(2c), R^(20c),R^(21c), R^(22c), R^(23c), R^(24c) and R^(25c) are 1 to 3 substituentsselected from the group consisting of 1) C₁₋₆ alkyl, 2) C₂₋₆ alkenyl, 3)C₂₋₆ alkynyl, 4) C₃₋₇ cycloalkyl, 5) C₆₋₁₀ aryl which may be substitutedwith 1 to 3 substituents selected from the group consisting of C₁₋₆alkyl, amino, N—(C₁₋₆ alkyl)amino, N,N-di-(C₁₋₆ alkyl)amino, amidino,carbamoyl, N—(C₁₋₆ alkyl)carbamoyl, N,N-di-(C₁₋₆ alkyl)carbamoyl,sulfamoyl, N—(C₁₋₆ alkyl)sulfamoyl, N,N-di-(C₁₋₆ alkyl)sulfamoyl,carboxyl, C₂₋₇ alkoxycarbonyl, hydroxyl, C₁₋₆ alkoxy, mercapto, C₁₋₆alkylthio, sulfo, cyano, azido, halogen, nitro, nitroso, phosphono, C₁₋₆alkoxyphosphoryl, di-(C₁₋₆ alkoxy)phosphoryl and C₁₋₆ alkyl substitutedwith phosphono, C₁₋₆ alkoxyphosphoryl and di-(C₁₋₆ alkoxy)phosphoryl(hereinafter the group of 5) is referred to as group “C”), 6) aromaticheterocyclic group selected from (a) aromatic 5- or 6-memberedheterocyclic group having 1-4 hetero atoms selected from nitrogen atom,oxygen atom and sulfur atom, (b) fused bicyclic heterocyclic groupformed by condensation of an aromatic 5- or 6-membered heterocyclicgroup having 1 to 3 hetero atoms selected from nitrogen atom, oxygenatom and sulfur atom with benzene ring or an aromatic 5- or 6-memberedheterocyclic group having 1 to 3 hetero atoms selected from nitrogenatom, oxygen atom and sulfur atom and (c) fused tricyclic heterocyclicgroup formed by condensation of [1] an aromatic 5- or 6-memberedheterocyclic group having 1-3 hetero atoms selected from nitrogen atom,oxygen atom and sulfur atom, [2] benzene ring, and [3] an aromatic 5- or6-membered heterocyclic group having 1-3 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom or benzene ring, 7)heterocyclic-oxy group formed by combining each of the above aromaticheterocyclic groups (a), (b) and (c) with oxy group, 8) non-aromatic 4-or 7-membered heterocyclic group having 1 to 3 hetero atoms selectedfrom nitrogen atom, oxygen atom and sulfur atom, 9) C₇₋₁₄ aralkyl whichmay be substituted with 1 to 3 substituents selected from the group “C”,10) amino group, 11) N-mono-substituted amino selected from N—(C₁₋₆alkyl)amino, N—(C₂₋₆ alkenyl)amino, N—(C₃₋₇ cycloalkyl)amino group andN—(C₆₋₁₀ aryl)amino which may be substituted with 1 to 3 substituentsselected from the group “C”, 12) amino substituted with two substituentsselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkenyl and C₆₋₁₀ arylwhich may be substituted with 1 to 3 substituents selected from thegroup “C”, 13) amidino, 14) acyl selected from C₂₋₈ alkanoyl, C₃₋₈alkenoyl, C₃₋₇ cycloalkyl-carbonyl, C₃₋₇ cycloalkenyl-carbonyl, C₆₋₁₀aryl-carbonyl which may be substituted with 1 to 3 substituents selectedfrom the group “C”, and heterocyclic-carbonyl formed by binding of anaromatic or non-aromatic 5- or 6-membered heterocyclic group having 1-3hetero atoms selected from nitrogen atom, oxygen atom and sulfur atomwith carbonyl, 15) carbamoyl, 16) mono-substituted carbamoyl groupselected from N—(C₁₋₆ alkyl)carbamoyl, N—(C₂₋₆ alkenyl)carbamoyl,N—(C₃₋₇ cycloalkyl)carbamoyl and N—(C₆₋₁₀ aryl)carbamoyl which may besubstituted with 1 to 3 substituents selected from the group “C”, 17)carbamoyl substituted with two substituents selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₃₋₇ cycloalkyl and C₆₋₁₀ aryl which may be substitutedwith 1 to 3 substituents selected from the group “C”, 18) sulfamoyl, 19)N-mono-substituted sulfamoyl selected from N—(C₁₋₆ alkyl)sulfamoyl,N—(C₂₋₆ alkenyl)sulfamoyl, N—(C₃₋₇ cycloalkyl)sulfamoyl and N—(C₆₋₁₀aryl)sulfamoyl which may be substituted with 1 to 3 substituentsselected from the group “C”, 20) sulfamoyl substituted with twosubstituents selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl andC₆₋₁₀ aryl which may be substituted with 1 to 3 substituents selectedfrom the group “C”, 21) carboxyl, 22) C₁₋₆ alkoxy-carbonyl, 23)hydroxyl, 24) C₁₋₆ alkoxy, 25) C₂₋₁₀ alkenyloxy, 26) C₃₋₇ cycloalkyloxy,27) C₆₋₁₀ aryloxy which may be substituted with 1 to 3 substituentsselected from the group “C”, 28) C₇₋₁₄ aralkyloxy which may besubstituted with 1 to 3 substituents selected from the group “C”, 29)mercapto, 30) C₁₋₆ alkylthio, 31) C₇₋₁₄ aralkylthio which may besubstituted with 1 to 3 substituents selected from the group “C”, 32)C₆₋₁₀ arylthio which may be substituted with 1 to 3 substituentsselected from the group “C”, 33) C₁₋₆ alkylsulfinyl, 34) C₇₋₁₄aralkylsulfinyl which may be substituted with 1 to 3 substituentsselected from the group “C”, 35) C₆₋₁₀ arylsulfinyl which may besubstituted with 1 to 3 substituents selected from the group “C”, 36)C₁₋₆ alkylsulfonyl, 38) C₇₋₁₄ aralkylsulfonyl which may be substitutedwith 1 to 3 substituents selected from the group “C”, 39) C₆₋₁₀arylsulfonyl which may be substituted with 1 to 3 substituents selectedfrom the group “C”, 40) sulfo, 41) cyano, 42) azido, 43) halogen, 44)nitro, 45) nitroso, 46) phosphono, 47) C₁₋₆ alkoxy-phosphoryl 48)di-C₁₋₆ alkoxy-phosphoryl, 49) C₁₋₆ alkyl substituted with phosphono,C₁₋₆ alkoxyphosphoryl or di-(C₁₋₆ alkoxy)phosphoryl 50) C₁₋₆ alkylsubstituted with 1 to 4 halogen atoms 51) C₁₋₆ alkoxy substituted with 1to 4 halogen atoms and 52) C₁₋₆ alkylenedioxy (hereinafter the group ofabove 1) to 52) is referred to as group “B”); R³ is H, a C₁₋₆ alkylgroup or a C₇₋₁₄ aralkyl group; Y is CH; R⁸ is H, a C₁₋₆ alkyl group, aC₁₋₆ alkylthio group or a C₁₋₆ alkoxy group which may be substitutedwith hydroxyl group; Ar is (1) a C₆₋₁₀ aryl group, (2) a 5- to7-membered aromatic or non-aromatic heterocyclic group having 1-4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, or (3) aC₃₋₇ saturated or unsaturated alicyclic hydrocarbon group, each of whichmay be substituted with 1 to 3 substituents selected from the group “B”;one of R⁹ and R¹⁰ is a hydrogen atom or C₁₋₆ alkyl group which may besubstituted with 1 to 3 substituents selected from the group “B” and theother is (1) a hydrocarbon group selected from C₁₋₈ saturated aliphatichydrocarbon group, C₂₋₈ unsaturated aliphatic hydrocarbon group, C₃₋₇saturated alicyclic hydrocarbon group, C₃₋₇ unsaturated alicyclichydrocarbon group, C₉₋₁₀ partly saturated and fused bicyclic hydrocarbongroup, C₃₋₇ saturated or unsaturated alicyclic-C₁₋₈ saturated orunsaturated aliphatic hydrocarbon group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon-C₁₋₄ alkyl group, C₉₋₁₀ partly saturated andfused bicyclic hydrocarbon-C₂₋₄ alkenyl group, C₆₋₁₀ aryl group andC₇₋₁₄ aralkyl group, each of which may be substituted with 1 to 3substituents selected from the group “B” or (2) a 5- to 7-memberedaromatic or non-aromatic heterocyclic group having 1-4 hetero atomsselected from nitrogen atom, oxygen atom and sulfur atom, which may besubstituted with 1 to 3 substituents selected from the group “B”, or R⁹and R¹⁰ may be combined to form a C₅₋₇ carbon ring; and X³ is CH₂. 14.The compound according to claim 8, wherein R¹ is a group of the formula:—CONR²⁰(CR²¹R²²R²³) (wherein R²⁰ is H, and R²¹, R²², and R²³ are thesame or different and are an optionally substituted hydrocarbon group oran optionally substituted heterocyclic group); R³ is H; Ar is anoptionally substituted aromatic ring group; X³ is CH₂; Y is CH; R⁸ is Hor an optionally substituted hydrocarbon group, an optionallysubstituted alkoxy group, an optionally substituted sulfanyl group, anoptionally substituted sulfinyl group, or an optionally substitutedsulfonyl group, C₁₋₆ alkoxy-carbonyl; and R⁹ and R¹⁰ are the same ordifferent and are an optionally substituted hydrocarbon group.
 15. Thecompound according to claim 14, wherein at least one of R²¹, R²², andR²³ is an optionally substituted heterocyclic group or an optionallysubstituted phenyl group.
 16. The compound according to claim 14,wherein R²⁰ and R²¹ are combined to form an optionally substituted 5- to7-membered ring, and R²² and R²³ are the same or different and are anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group, or an optionally substituted phenyl group.
 17. Thecompound according to claim 14, wherein R²¹ and R²² are the same ordifferent and are a C₁₋₈ hydrocarbon group, and R²³ is an optionallysubstituted 5-membered heterocyclic group which may be fused with anoptionally substituted benzene ring, or an optionally substituted phenylgroup.
 18. The compound according to claim 16, wherein R²⁰ and R²¹ arecombined to form a 5- or 6-membered ring which may be fused with benzenering and/or substituted with 1 to 3 substituents selected from the groupconsisting of (1) halogen, (2) hydrogen, (3) a phenoxy which may besubstituted with 1 to 3 substituents selected from halogen, hydroxyl,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl, cyano, amino, mono-C₁₋₆ alkyl-amino,di-C₁₋₆ alkyl-amino, C₁₋₆ alkyl-sulfanyl, C₁₋₆ alkyl-sulfinyl, C₁₋₆alkyl-sulfonyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, N—C₁₋₆ alkyl-carbamoyland N,N-di-C₁₋₆ alkyl-carbamoyl, (4) C₁₋₆ alkoxy which may besubstituted with 1 to 3 substituents selected from halogen, hydroxyl,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl, cyano, amino, mono-C₁₋₆ alkyl-amino,di-C₁₋₆ alkyl-amino, C₁₋₆ alkyl-sulfanyl, C₁₋₆ alkyl-sulfinyl, C₁₋₆alkyl-sulfonyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, N—C₁₋₆ alkyl-carbamoyl,N,N-di-C₁₋₆ alkyl-carbamoyl and phenyl which may be substituted with 1to 3 substituents selected from halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ acyl, cyano, halogeno C₁₋₆ alkyl, amino, mono-C₁₋₆alkyl-amino, di-C₁₋₆ alkyl-amino, C₁₋₆ alkyl-sulfanyl, C₁₋₆alkyl-sulfinyl, C₁₋₆ alkyl-sulfonyl, C₁₋₆ alkoxy-carbonyl, carbamoyl,N—C₁₋₆ alkyl-carbamoyl and N,N-di-C₁₋₆ alkyl-carbamoyl, and (5) a C₁₋₈hydrocarbon group which may be substituted with 1 to 3 substituentsselected from halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ acyl,cyano, amino, mono-C₁₋₆ alkyl-amino, di-C₁₋₆ alkyl-amino, C₁₋₆alkyl-sulfanyl, C₁₋₆ alkyl-sulfinyl, C₁₋₆ alkyl-sulfonyl, C₁₋₆alkoxy-carbonyl, carbamoyl, N—C₁₋₆ alkyl-carbamoyl, N,N-di-C₁₋₆alkyl-carbamoyl and phenyl which may be substituted with 1 to 3substituents selected from halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ acyl, cyano, halogeno C₁₋₆ alkyl, amino, mono-C₁₋₆ alkyl-amino,di-C₁₋₆ alkyl-amino, C₁₋₆ alkyl-sulfanyl, C₁₋₆ alkyl-sulfinyl, C₁₋₆alkyl-sulfonyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, N—C₁₋₆ alkyl-carbamoyland N,N-di-C₁₋₆ alkyl-carbamoyl, and R²² and R²³ are the same ordifferent and C₁₋₈ hydrocarbon group which may be substituted with 1 to3 substituents selected from halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ acyl, cyano, amino, mono-C₁₋₆ alkyl-amino, di-C₁₋₆ alkyl-amino,C₁₋₆ alkyl-sulfanyl, C₁₋₆ alkyl-sulfinyl, C₁₋₆ alkyl-sulfonyl, C₁₋₆alkoxy-carbonyl, carbamoyl, N—C₁₋₆ alkyl-carbamoyl, N,N-di-C₁₋₆alkyl-carbamoyl and phenyl which may be substituted with 1 to 3substituents selected from halogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ acyl, cyano, halogeno C₁₋₆ alkyl, amino, mono-C₁₋₆ alkyl-amino,di-C₁₋₆ alkyl-amino, C₁₋₆ alkyl-sulfanyl, C₁₋₆ alkyl-sulfinyl, C₁₋₆alkyl-sulfonyl, C₁₋₆ alkoxy-carbonyl, carbamoyl, N—C₁₋₆ alkyl-carbamoyland N,N-di-C₁₋₆ alkyl-carbamoyl.
 19. (canceled)
 20. (canceled)
 21. Aprodrug of the compound according to claim
 1. 22. A pharmaceuticalcomposition which comprises the compound according to claim 1, or aprodrug thereof.
 23. A composition for modulating calcium receptor whichcomprises a compound of the formula (I):

wherein ring A is an optionally substituted 5- to 7-membered ring; ringB is an optionally substituted 5- to 7-membered heterocyclic ring; X¹ isCR¹ (wherein R¹ is H, an optionally substituted hydrocarbon group, anoptionally substituted hydroxyl group, an optionally substituted aminogroup, an optionally substituted thiol group, cyano group, a halogenatom, an optionally substituted heterocyclic group, or a group of theformula: -Z¹-Z² (wherein -Z¹- is —CO—, —CS—, —SO— or —SO₂—, and Z² is anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group, an optionally substituted hydroxyl group, or anoptionally substituted amino group)), CR¹R² (wherein R¹ is as definedabove, R² is H or an optionally substituted hydrocarbon group), N orNR¹³ (wherein R¹³ is H, an optionally substituted hydrocarbon group, anoptionally substituted hydroxyl group, an optionally substituted aminogroup, cyano group, a halogen atom, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above)); X² is N or NR³ (wherein R³ is H, anoptionally substituted hydrocarbon group, an optionally substitutedhydroxyl group, an optionally substituted amino group, cyano group, ahalogen atom, an optionally substituted heterocyclic group, or a groupof the formula: -Z¹-Z² (wherein -Z¹- and Z² are as defined above); Y isC, CR⁴ (wherein R⁴ is H, an optionally substituted hydrocarbon group, anoptionally substituted hydroxyl group, an optionally substituted aminogroup, an optionally substituted thiol group, cyano group, a halogenatom, an optionally substituted heterocyclic group, or a group of theformula: -Z¹-Z² (wherein -Z¹- and Z² are as defined above)) or N; Z isCR⁵ (wherein R⁵ is H, an optionally substituted hydrocarbon group, anoptionally substituted hydroxyl group, an optionally substituted aminogroup, an optionally substituted thiol group, cyano group, a halogenatom, an optionally substituted heterocyclic group, or a group of theformula: -Z¹-Z² (wherein -Z¹- and Z² are as defined above)), CR⁵R⁶(wherein R⁵ and R⁶ are the same or different and are H, an optionallysubstituted hydrocarbon group, an optionally substituted hydroxyl group,an optionally substituted amino group, an optionally substituted thiolgroup, cyano group, a halogen atom, an optionally substitutedheterocyclic group, or a group of the formula: -Z¹-Z² (wherein -Z¹- andZ² are as defined above)), N or NR⁷ (wherein R⁷ is H, an optionallysubstituted hydrocarbon group, an optionally substituted hydroxyl group,an optionally substituted amino group, cyano group, a halogen atom, anoptionally substituted heterocyclic group, or a group of the formula:-Z¹-Z² (wherein -Z¹- and Z² are as defined above)); Ar is an optionallysubstituted cyclic group; R is H, an optionally substituted hydrocarbongroup, an optionally substituted hydroxyl group, an optionallysubstituted amino group, an optionally substituted thiol group, anoptionally substituted sulfonyl group or an optionally substitutedsulfinyl group, or R and Z may be combined to form a ring B; and

is a single bond or a double bond; or a salt thereof or a prodrugthereof.
 24. The composition according to claim 23, which is a calciumreceptor antagonist.
 25. The composition according to claim 23, which isan agent for preventing or treating diseases caused by abnormality ofcalcium concentration in a living body or a calcium receptor.
 26. Thecomposition according to claim 23, which is an agent for preventing ortreating bone diseases.
 27. The composition according to claim 23, whichis an agent for preventing or treating osteoporosis or fracture.
 28. Amethod for modulating a calcium receptor which comprises administeringto a mammal an effective amount of a compound of the formula (I) or asalt thereof or a prodrug thereof according to claim
 23. 29. A methodfor preventing or treating bone diseases, which comprises administeringto a mammal an effective amount of a compound of the formula (I) or asalt thereof or a prodrug thereof according to claim
 23. 30. (canceled)31. (canceled)